Keeping the calcium:phosphorus solubility product ... - RM Solutions

Keeping the calcium:phosphorus solubility product ... - RM Solutions

Parenteral Nutrition Formulations:

What we do not know?


Ashraf Salem Al Alwan, PhD

Consultant Clinical Pharmacist (PN)

Assistant Director of Pharmacy For Clinical


Pharmacist Responsibilities

‣ Pharmacist needs to be able to recognize when the amount of

nutrient ordered for a patient is NOT within an acceptable

standard range.

‣ The ordered quantity of protein, carbohydrate, fat, electrolytes,

fluid, vitamins, and trace elements should all be assessed for

appropriateness before they are compounded.

‣ Acceptable ranges for each of these nutrients should be based



stability, and

normal clinical requirements.

Pharmacist Responsibilities cont.

‣ The standard nutrient ranges apply to Adult and Paediatric and

Neonate patients with normal organ function.

‣ PN solutions are prepared, labeled distributed, and stored in

the same manner as I.V solutions.

‣ All PN orders to pharmacy must be submitted on PN order

form only. The original copy of the filled form is sent to the

Pharmacy, with a copy kept in the patient’s chart.

‣ PN orders must not be written until the proper catheter position

has been checked on the post-insertion chest X-ray.

What should I know before mixing/ preparing PN?

‣ Knowledge of Hospital –PN strategies and policies.

‣ Knowledge of aseptic technique.

‣ Knowledge of calculations.

‣ Knowledge of types and concentrations of different components

of PN.

‣ Knowledge of patient’s other medications e.g. Propofol.

‣ Knowledge of patient’s laboratory-profile.

‣ Technical training.

‣ Quality-controlled equipment e.g. LAFH, compounder,

computer, software.

‣ Continuous supply of standard items and materials.

‣ Controlled transport and delivery system.

Parenteral Nutrition Prescriptions

‣ PN formulations should be designed to meet the estimated

nutrition requirements for each individual patient.

‣ The ordered quantity of protein, carbohydrate, fat,

electrolytes, fluid, vitamins, and trace elements should all be

assessed for appropriateness before they are compounded.

‣ Acceptable ranges for each of these nutrients should be

based on compatibility, stability, and normal clinical

requirements. Serious disorders have been attributed to PN

formulations having inappropriate nutrient compositions.

Parenteral Nutrition Prescriptions cont.

‣ Traditionally, the pharmacist is assigned the responsibility of

verifying the indication, dose, and use of a drug or nutrient, as is

the case with PN.

‣ Some hospitals requiring that the PN prescription be rewritten

each day, the potential exists for transcription errors that omit or

significantly increase nutrient doses.

‣ Some computer software for PN admixture may be

programmed to clue the pharmacist that the PN admixture is

inappropriate when nutrient doses are outside an acceptable


‣ Others however, may find it helpful to develop order forms for

standard PN formulations that apply to specific patient

populations with normal organ function.

Calcium and Phosphate

• Preterm infants, children born before 37 weeks of pregnancy,

are the major recipients of parenteral nutrition therapy.

• Preterm infants frequently intolerant to enteral feeding due to

anatomic and functional immaturity of the digestive tract, added

to other clinical conditions that affect cardiovascular function in

the preterm post-natal life [1,2,3]

1. Philip AGS. Pediatr Res 2005, 58, 799=815.

2. Fanaro S, Cristofori G, Mosca F, Savino F, Vigi V. Acta Paediatr Suppl 2005, 94, 75-63.

3. Kalhan CS, Iben S: Clin Perinatol 2000, 27:23-55.

• These patients need a Ca/PO 4 ratio higher than 1 (42 mg/Kg/d

Ca and 36 mg/Kg/d P) in order to allow bone mineralization.

• Studies on calcium and phosphorus retention in neonates

propose that 1.7/1 (75 mg/Kg/d Ca and 45 mg/Kg/d P)

calcium/phosphorus ratio is closer to that observed for intrauterine

life, allowing greater retention of these ions (1)

• This ratio is difficult to obtain with parenteral feeding, because

the availability of these ions offer is limited by their salts

solubility in the formulation (2) .

1. Devlieger H, etal. E. Clin Nutr 1993, 12, 277-281.

2. Rigo J, Senterre J: Nutritional needs of premature infants: current issues. J Pediatr 2006, 149:S80-S88.

Depiction of dibasic calcium phosphate

in parenteral nutrition admixtures

Method: Final AA concentrations of 1%, 2%, or 3% (n = 3 levels), with fixed concentrations of other nutrients

(5% G, 60 mmol/L sodium, 40 mmol/L potassium, 2.5 mmol/L magnesium, 3 mL of trace minerals, and 10 mL

of multivitamins [all n = 1 level]; along with either 2.5 or 5 mmol/L [5 or 10 mEq/L] of Ca [n = 2 levels] with 15

or 30 mmol/L of P [n = 2 levels]), were tested for a total of 12 base (3 × 2 × 2) formulations as shown in Table 1.

The 2 levels of Ca and P were equal to 50% and 100%, respectively, of the approximate parenteral equivalent of the

recommended dietary amounts of each mineral

a) Different crystal granules found in TPN solutions containing calcium gluconate

and Phocytan ( at various concentrations ) after 18 hours of storage at C؛‎37±1‎ + 24

hours at ambient temperature (Sizes varied from 2 μm to 50 μm )

b) Particles observed at calcium gluconate ( 60 mmol/L ) and Phocytan ( 80 mmol/L)

after 24hours at C؛‎37±1‎ ( Sizes varied from 25 μm to 60 μm )

Inorganic phosphate (as dibasic potassium phosphate: K2HPO4) was prepared at a concentration of 0.57

mmol/mL by dissolving 100 g of K2HPO4 powder (Merck) in 1000 mL of distilled water. An organic source of

phosphorus was provided by Phocytan (glucose-1-phosphate) containing 0.33 mmol/mL of phosphorus

(Aguettant, France). Calcium gluconate at 10% (Glucalcium Renaudin, France) was used as an organic calcium

source, whereas calcium chloride (CaCl2) solutions were prepared in the laboratory

Factors affecting TPN Compatibility

• The compatibility depends on factors such as:

‣ Solution pH

‣ Temperature

‣ Material of the parenteral nutrition container

‣ Oxygen

‣ Light exposure

‣ Composition of trace elements

‣ Presence of vitamins

‣ Peroxidation

‣ Relative concentration of each ion, and order of addition of

divalent ions such as calcium

• The risk of TNA destabilization may be reduced by:

Keeping the final amino acid concentration at 2.5% or greater.

• Maintaining a final pH of 5.0 or above.

Keeping the final dextrose concentration at 3.3% or greater.

• Avoiding trivalent cations (Iron dextran).

• Avoiding mixing dextrose and lipid directly.

• Add lipid last, after all other components (except vitamins) are mixed.

pH Effects

• The pH of the final admixture is important as a factor that

directly influences the ionization of the lipid globule

phospholipids, and also interferes in the dissociation of ions in


• The higher the concentrations of AA and glucose, the greater

the amount of Ca and PO 4 that can be mixed in the solution

without causing precipitation.

• Organic phosphates have been recommended as sources of

phosphorus in PN solutions for premature infants because of

their higher compatibility with calcium than inorganic


• There is little evidence that degradation of drugs or nutrients

results in serious clinical harm. However, serious harm can

occur when an incompatible PN formulation results in the

development of precipitates exceeding 5–7µm in size.

• If allowed to enter the systemic circulation, particles of this

size are capable of obstructing blood flow through the

pulmonary capillaries leading to pulmonary embolism.

• Since the eye can only detect particles greater than 50

µm in size, one cannot rely on visual inspection of the

formulation to ensure compatibility of the ingredients.

• The development of large particles can result from an

incompatible combination of various salts added to a PN


Oxidized lipids and Secondary peroxidation products

• The infusion of oxidized lipids and secondary peroxidation

products can be extremely cytotoxic, and may cause many

disorders, such as:

• Hepatic steatosis [1]

• Hyper triglyceridemia [2]

• Increase in vascular resistance in the lung [3]

• Lung remodeling [4]

• Chronic lung diseases of prematurity [5,6]

1. Chessex P et al., Pediatr Res 2002, 52:958-963.

2. Khashu M et al. Arch Dis Child Fetal Neonatal 2009, 94:F111-F115.

3. Prasertsom W et al. Arch Dis Child 1996, 74:F95-98.

4. Lavoie JC, et al. Pediatric Pulmonology 2005, 40:53-56.

5. Chessex P et alJ Pediatr 2007, 151:213-214.

6. Bassiouny MR et al J Pediatr Gastroenterol Nutr 2009, 48:363-369.

• TPN is a potential source of oxidants and this is particularly

dangerous in preterm infants who are vulnerable to oxidative

stress [1,2].

• in the neonatology, the peroxide formation caused by exposing

TPN admixtures to phototherapy is well-known [3,4].

• Physical protection of the light incidence in TPN admixtures

leads to formation of even lower concentrations of peroxides

than the usual photo protection.

1. Lavoie JC et al. Pediatrics 1997, 9(3):e61-5.

2. Saugstad OD Biol Neonate 2005, 88:228-236.

3. Laborie S et al. J Pediatr 2000, 136:628-32.

4. Neuzil J et al. J Pediatr 1995, 126(5):785-790

Lipid Emulsions/Structured Lipids

• IV lipid emulsions available are composed solely of long-chain

triglycerides (LCT, carbon chain length >14).

• Mixtures of medium-chain triglycerides (MCT, carbon chain

length 6–12) and LCT.

• Such formulations may be of use in patients intolerant to long

chain lipid products during critical illness and metabolic stress,

and also in pediatric patients with carnitine deficiency.

• New Generation Fat Emulsions (SMOF Fat Emulsions):

• Limited soya bean oil (max. 30%), MCT and Olive oil, fish oil

(rich in long chain Ω-3 fatty acids = potential to reduce

inflammatory and thrombotic responses, while protecting

microperfusion and immunity)

• Fat sources used in the manufacture of IV lipid emulsions are:

• Typically: Soybean Oil (10%, 20%, or 30%) or

• Combinations: (50:50 mix) of Safflower and Soybean


• Major fatty acid components include and range from:

• 44% to 65.8% linoleic acid

• 19% - 30% oleic acid.

• 7% - 14% palmitic acid.

• 4% - 11% linolenic acid.

• 1.4% - 5.5% stearic acid.

• Other components of lipid emulsions include:

• Egg yolk phospholipid as an emulsifier

• Glycerin to render the formulation isotonic

• Vitamin K

• Sodium

• Concerns for the potential of lipid emulsions to support

bacterial and fungal growth (if contaminated) led to Centers for

Disease Control and Pevention (CDC) guidelines limiting the

hang times of lipid emulsions given in the piggyback fashion to

a maximum of 12 hours.

• At times, and with faster infusion rates (over 4–6 hours), this

has predisposed susceptible patients to hypertriglyceridemia

that could be lessened by infusing the lipid at a slower rate

over a longer period of time.

• Initial concerns for increased risk of infection due to hanging

the lipid longer than 12 hours have not been realized with

adherence to proper sterile technique at all points in the

preparation and administration.

• Either system may be infused via central access.

• If PN is to be administered via a true peripheral access certain

criteria are important to decrease risk of phlebitis and damage

to peripheral vein(s).

Osmolarity: The Big Question?

• Osmolarity should generally be kept below 900 mOsm/L.

• Calcium and potassium Conc. may also be kept low (for

some institutions, this may translate to calcium

• In neonatology, for central access, the osmolarity level must

be kept at around 800 mOsm/L, not exceeding twice the

regular serum osmolarity [1].

• High osmolarity arises from high ion concentrations as well

as glucose, and the ionic components may also affect the

lipid globule stabilization.

Driscoll DF et al. Clin nutr 2003, 22, 485-495.

Peroxide Formation

• It has been shown that TPN admixtures in multilayered bag

present less oxidation evaluated by hydroperoxide formation


• TPN bag has low oxygen permeation and could be collapsed to

eliminate, as much as possible, the oxygening the bag.

• Moreover, the presence of amino acids [3,4] in formulations

containing trace elements, lipids and vitamins [5] decrease the

peroxide formation and its clinical complications [3,6].

1. Steger PJK, Muhlebach SF. Nutr 1997, 13 (2), 133-140.

2. Balet A et al. J Parenter Enteral Nutr 2004, 28:85-91.

3. Lavoie JC et al.. Pediatrics 1997, 99(3):e61-5.

4. Bhatia J et al.. J Pediatr 1980, 96, 284-286.

5. Silvers KM et al. Acta Paediatr 2001, 90(3):242-249

6. Lavoie JC et al.. Pediatric Pulmonology 2005, 40:53-56

• During the 6 hours after TPN preparation the balance between

generation and consumption of peroxides is positive, and after

this time they presume that the balance changed in favor of the

consumption, during their transformation into free radicals via

the Fenton-like reaction induced by trace elements present in

the PN solution. [1]

• Although it was shown that the vitamin solutions cause more

peroxidation, some vitamins have been shown to have

antioxidant effects, as vitamin C.

• The oxidation of amino acids and vitamin C could prevent the

lipid peroxidation turning the peroxidation undetectable.

1. Lavoie JC et al. 1997 Admixture of a multivitamin preparation to parenteral nutrition: The major contributor to in

vitro generation of peroxides. Pediatrics, 99(3):e61-5.

• The physical stability of the lipid emulsions can be improved

by using surfactants that form a coalescence energy barrier

that carries electric charges around the dispersed liquid,

aiming at decreasing the surface tension and increasing the

repulsion force between the dispersed liquids.

• In the case of TPN admixtures containing egg lecithin as

anionic emulsifier, the lecithin produces a negative charge

around the lipid globules through the ionization of the

phosphate groups.

• Any positively charged ion, such as calcium, could cause

irreversible instability in this system, neutralizing the negative

phospholipids droplets and promoting coalescence [1].

1. Driscoll DF: Pharm Res 2006, 23:1959-1969

Stages of TPN destabilization:

1. Creaming: accumulation of triglyceride particles at the top of the


2. Aggregation: clumping of triglyceride particles within the emulsion.

3. Coalescense: fusion of small triglyceride particles into larger


4. Cracking: separation of the oil and water components of the


Mixing: 3 in 1 vs 2 in 1?


• All components aseptically compounded by the pharmacy

• Preparation is more efficient for pharmacy personnel, especially

if automated

• Less manipulation of the system during administration

• Less risk of contamination during administration

• More convenient storage, fewer supplies, easier administration

in home care settings

• Glucose and venous access tolerance may be better in some


• Possible applications in fluid-restricted patients

• May be more cost-effective overall in certain settings

• Less nursing time needed for 1 bag/d and no piggyback to


• Less supply and equipment expense for only 1 pump and IV


• Less nursing time needed for 1 bag/d and no piggyback to


• Less supply and equipment expense for only 1 pump and IV


• More convenient storage, fewer supplies, easier administration

in home care settings.

• Glucose and venous access tolerance may be better in some


• Possible applications in fluid-restricted patients.

• May be more cost-effective overall in certain settings.


• Larger particle size of admixed lipid emulsion precludes use of

0.22-micron (bacteria-eliminating) filter, and requires larger pore

size filter of 1.2 micron.

• Admixed lipid emulsion less stable, more prone to separation of

lipid components

• Admixtures are more sensitive to destabilization with certain

electrolyte concentrations

• Difficult to visualize precipitate or particulate material in the

opaque admixture

• Certain medications are incompatible with lipid emulsion portion

of admixture

• Catheter occlusion more common with daily lipid administration

• Less attractive in pediatric settings due to pH and

compatibility considerations.

• Admixtures are more sensitive to destabilization with

certain electrolyte concentrations.

• Difficult to visualize precipitate or particulate material in

the opaque admixture.

• Certain medications are incompatible with lipid emulsion

portion of admixture.

• Catheter occlusion more common with daily lipid


• Less attractive in pediatric settings due to pH and

compatibility considerations.

Temperature effect

Number of globules counted for each bar, use of Optical Microscopy (OM):

Bar graphs represent the mean and standard deviation of the diameter of lipid globules present in

admixtures PC, P1 and P2 stored at 25°C, 4°C and 37°C, during seven days of study D0 - D7 (n = 2 lots).

The calcium/phosphorus ratios for P1 and P2 admixtures are (calcium and phosphorus) 2/1 and 4/1,

respectively, and the control parenteral nutrition (PC) is free of calcium.

Order of mixing

add Dextrose, amino acid and water (if any).

add phosphorus.

add sodium, potassium and magnesium.

add trace element ⇒ agitate.

add calcium ⇒ agitate well.

observe for precipitation, if YES ⇒ discard.

If NO, add lipid ⇒ agitate ⇒ observe if cracking.

add the multivitamin ⇒ agitate.

Osmolarity (mOsm/L) = [(grams dextrose / liter) x 5] + [grams amino acid / liter) x 10] + [(mEq cations / liter) x 2]

Predicted serum osmolality = 2 Na + [glucose (mg/dl) / 18] + [BUN (mg/dl)/ 2.8]

One Method to Calculate Osmolarity of IV Admixtures

1. First, multiply the gm, mEq or mL by the mOsm/unit listed below.

2. Add all the multiplied values to determine the total mOsm for the mixture.

3. Add each volume in the formulation to give a total in liters.

4. Divide the total mOsm by the total volume in liters to determine the mOsm/L of the formulation

Daily Energy and Substrate Guidelines for Adult PN



‣ Refeeding

‣ Obesity (≥130% IBW)

Acute Care

25–30 total kcals/kg/d

15–25 kcal/kg/d

15–20 kcal/kg/d adjusted weight *

Critical Care

25 total kcals/kg/d

15–25 kcal/kg/d

15–20 kcal/kg/d adjusted weight *




0.8–1.0 g/kg/d maintenance

1.2–2.0 g/kg/d catabolism

Review of Access Devices Used for

Nutritional Support

Take Home Message

• The presence of large calcium phosphate crystals may occlude

pulmonary arterioles as well as catheters, leading to potentially lifethreatening


• To solve the problem:

First method: involves separate infusion of the solutions

containing Ca and PO 4 .

Second method: is the addition of L-cysteine hydrochloride,

because decreasing the pH of the solution promotes the

compatibility of Ca and PO 4 .

Third method: the use of organic calcium salts (calcium

gluconate or calcium gluceptate) and organic phosphate (sodium

glycerophosphate or glucose- 1-phosphate) allows the addition of

higher concentrations of both electrolytes.

Factors which affect the formation of calcium phosphate, including:

‣ Amino acid concentration

‣ pH of the formulation

‣ Temperature

Remember that 1 mMol of phosphate = 2 mEq

‣ Calcium salt used

‣ Order of mixing

‣ Concentration of the electrolytes

‣ The risk of precipitation may be reduced by:

Keeping the final amino acid concentration at 2.5% or greater.

Maintaining a final pH of 6.0 or lower.

Infusing the solution within 24 hours of preparation.

Using calcium gluconate instead of calcium chloride.

Avoiding mixing calcium and phosphorus in close sequence during preparation.

Keeping the calcium:phosphorus ratio 1:2.

Keeping the total amount of calcium and phosphorus less than 45 mEq/L.

Keeping the calcium:phosphorus solubility product less than 150.

Adding cysteine to the amino acids.

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