Parenteral nutrition (PN) regimens:
(a) standardized regimens, via peripheral veins (hypocaloric)
(b) standardized regimens, via central veins (normocaloric)
(c) patient-tailored regimens
Standardized TPN
Regimens (a) and (b) are typically used in metabolically stable general
medical / surgical patients requiring nutrition support.
Standardized TPN is provided for 70-90% of patients requiring nutrition
support depending on hospital type using standardized All-in-one (AIO)
admixtures to supply amino acids, carbohydrates, electrolytes, and fat.
These regimens can be purchased as "ready to use" admixtures
(Nutriflex® 2 chamber bag; NuTRIflex® lipid
3 chamber bag) from pharmaceutical companies or can be precompounded and
stored in the hospital pharmacy to be dispensed later on demand.
Patient-tailored regimens
Critically ill, significantly catabolic, frequently malnourished (ICU)
patients with compromised metabolic and organ functions (e.g. liver or
renal insufficient patients) require patient-tailored (central venous)
TPN because their nutrient requirements are high and tend to vary significantly
from patient to patient and during each patient's hospital course, calling
for daily regimen re-assembling in response to momentary needs and nutrient
utilization. AIO admixtures are a significant improvement over traditional,
cumbersome seperate bottle systems, allowing doctors to provide safe,
efficient, and labor-saving yet individualized TPN.
Hospital AIO admixture compounding services should focus on critical care
patients to optimize nutrition support efforts and maximize pharmacy resource
utilization.
Advantages of AIO admixtures for parenteral nutrition:
All in one, integral TPN system
All through one intravenous line
All by one infusion pump
Continuous and simultaneous infusion
Optimized nutrient utilization
Minimized manipulation needs both before and during the infusion-high
microbiologic safety
Minimized manipulation and monitoring needs significantly reduced
workload for nursing staff.
As a result of their physicochemical and pharmaceutical properties, AIO
admixtures are stable for only a few days to several weeks, depending
on their composition.
However, hospital-based compounding in compliance with the recommendations
described below efficiently produces safe, high-quality TPN admixtures.
In fact, the effort that goes into careful assembling and compounding
is amply rewarded by the multiple benefits of such an integral TPN system.
AIO admixtures should meet the same quality standards as the individual
pharmaceutical company-supplied PN solutions from which they are assembled.
Thus, hospital-compounded total nutrient admixtures must be sterile and
apyrogenic, and have well-defined composition and stability.
As compounded AIO mixtures cannot be sterilized for pharmaceutical reasons,
TPN bag filling must occur under aseptic conditions.
Compounding in the Hospital Pharmacy
To ensure aseptic handling and filling, PN solutions should always be
compounded in the hospital pharmacy. Also, the pharmacist has the professional
training, skills, expertise, and legal authorization to (pre)compound
and lay in a limited supply of pharmaceutical products in the pharmacy.
Resources committed to PN compounding services produce ample returns by
enhancing safety and efficiency as well as reducing monitoring needs and
the overall workload of the nursing staff.
Investigations in hospitals of different countries have revealed that
2-10% of hospital infusions showed evidence of microbial contamination
after administration, and this may be due to failure to use rigorously
aseptic technique for the large number of manipulations that had to be
performed before and during infusion.
AIO mixtures involve significantly fewer manipulations than do multibottle
TPN systems, reducing the manipulation-related risk of microbial contamination
on the ward.
Numerous studies have dealt with the growth rates of microorganisms in
hospital-compounded PN admixtures as compared to those in original infusion
solutions.
Gilbert et al. (5) studied the growth rates of various pathogens at 37°C
for 24 hours, comparing a pure fat emulsion with an amino acid-glucose
premixture and an AIO mixture.
Figure 1. Growth rates of various microorganisms in
PN solutions (modified from 5).
Little Microbial Growth in TPN Admixtures
It emerges from Figure 1 that all test organisms proliferated easily
in the fat emulsion but grew little in the amino acid-glucose premix,
and that microbial growth stopped or reversed in the TPN solution. Candida
albicans was the only microbe to show moderate growth also in the AIO
mixture. These results were confirmed by Jeppsson (6), who followed the
proliferation rate of Pseudomonas fluorescens in various media at 4°C
for several days. Figure 2 shows that the microorganism proliferated
in
the fat emulsion, while growth was stagnant in the TPN admixtur.
Figure 2. Microbial proliferation rate in infusion
solutions (modified from 6).
One reason for the difference in test organism growth rates between
original infusion solutions and AIO admixtures is the high osmolarity
of the latter.
Microbial growth is limited significantly by the high osmolarity of AIO
solutions as well as by some of the trace elements and electrolytes they
contain. However, a few microorganisms, such as specific fungi, also proliferate
in TPN admixtures at room temperature.
Figure 3. Growth of gram-positive bacteria and fungi
(left) and gram-negative bacteria (right) in TPN admixtures at 6°C
(modified from 4).
Storage at 4-8°C
Stored AIO admixtures should be inspected for microbial proliferation.
Fossum et al. (4) studied gram-positive and gram-negative bacterial and
fungal growth in refrigerated admixtures. It emerges from Figure 3 that,
under these conditions, none of the test organisms proliferated, and most,
in fact, perished. C. albicans, while remaining constant, failed to grow.
In conclusion, microorganisms in PN admixtures:
Show lower growth at room temperature compared with pure amino acid
solutions or fat emulsions
Perish or stagnate at 4-8°C.
Low Contamination Risk During TPN Mixture Compounding
Given the relatively low microbial proliferation risk in compounded admixtures,
what about the contamination risk during compounding?
Dirks et al. (1) tested 405 TPN bags filled by various pharmacists of
his pharmacy over a three-month period to validate TPN admixture compounding
and found that all admixtures were sterile, suggesting that TPN bag filling
using aseptic technique is safe. Aseptic filling can be validated by broth
filling for instance.
PN admixture components must be physicochemically compatible to rule
out degradation during the time from compounding through the end of the
infusion. The large number of diverse components in a typical TPN regimen
entail a significant risk of admixture incompatibility reactions. Typical
examples include:
Oxidation, precipitation, chemical interactions between amino acids
Maillard's reaction
Calcium phosphate precipitation
Incompatibility reactions are facilitated by such factors as exposure
to heat and/or light, length of storage, and presence of catalysts (e.g.,
trace elements), and the bag material may have a direct or - if permeable
to oxygen - indirect impact as well.
Maillard's Reaction
Reducing sugars react with amino acids to produce a yellow color (Maillard's
reaction). Basic amino acids such as lysine and histidine are the fastest
to react.
Maillard's reaction is a typical incompatibility reaction, and its rate
in PN solutions depends on:
reactant concentrations;
solution pH;
the length of storage;
the temperature prevailing during storage.
As a rule, the rate of Maillard's reaction decreases as the reactant
concentrations, admixture pH, temperature, and storage period decrease.
Amino acid solutions low in basic amino acids are slower to react than
those with a high concentration.
Calcium Phosphate Precipitation
Precipitation of calcium phosphate from PN solutions or admixtures is
a very familiar phenomenon and may present a hazard for the patients (3).
The lower the pH, the higher the proportion of monobasic calcium phosphate
and the lower the risk of crystallization. Conversely, the higher the
pH, the higher the proportion of dibasic calcium phosphate and the higher
the precipitation risk. Studies have evaluated the effect of pH on calcium
and phosphate limit concentrations in a typical PN regimen. Figure 4 depicts
the borderline between solubility und crystallization. Strictly speaking,
the reported values apply only to the tested regimen because the concentrations
of the other regimen components also have an impact - albeit a small one.
Figure 4. Calcium phosphate solubility as a function
of pH.
At a phosphate concentration of 10 mmol/L, approximately 10 mmol/L
of calcium can be added at pH 6.6, but as much as 35 mmol/L can be added
to this solution at pH 6.2. The maximum amounts of calcium and phosphate
that can still be added without causing precipitation cannot be predicted
because AIO admixture pH is determined by the mixture components and,
therefore, is difficult to control. While TPN solutions for adults rarely
exceed the calcium and phosphate limit concentrations within the usual
pH range of such mixtures, the risk of calcium phosphate precipitation
should always be borne in mind when compounding PN admixtures for children.
Stability of Vitamins
As a result of their complex molecular structure, vitamins tend to enter
into instability reactions when added to infusion solutions or TPN admixtures.
Martens studied the stability of selected water-soluble and fat-soluble vitamins
added to a typical TPN solution and exposed to diverse storage and administration
conditions (temperature, light, oxygen, trace elements, amino acids, bag
material).
Concentration loss was observed for:
Ascorbic acid (C)
oxygen and heat labile
Thiamine (B1)
thermolabile
Riboflavin (B2)
sensitive to light
Retinol (A)
sensitive to light
Vitamin C
Ascorbic acid was found to be particularly sensitive to various factors.
Figure 5 depicts the significant loss (up to 70% of added amount) seen
during the three-day study period.
Figure 5. Ascorbic acid stability in TPN admixtures. Impact of exposure
to light and
trace
elements (modified from 7).
Given these study results, vitamins should not be added to PN admixtures
until immediately before the start of an infusion, ensuring adequate
protection from light.
3.1Expected Shelf Life for TPN
admixtures depending on the regimens' composition
General Guidelines
PN admixtures - depending on their composition - are stable for several
days or even some months. However, admixture stability is extremely
susceptible to even minute formulation changes, so the shelf life cannot
be predicted with a 100% accuray. Stability testing is therefore all
but mandatory.
Because of the degradation of vitamins during storage, it is recommended
to add the vitamins prior to use.
Nonnutrient drugs should not usually be added (but may be compatible,
as demonstrated for cimetidine and ranitidine for instance).Frequently
used admixture formulations should be tested for compatibility in the
laboratory beforehand.
During filling of the bag, please keep to the following sequence:
amino acids?
glucose?
electrolytes?
trace elements?
fat emulsion
Fat emulsions are thermodynamically sensitive pharmaceutical products,
and their utility depends on both chemical and physical stability. As
a result, fat emulsion quality is essentially determined by lipid droplet
size and distribution.
Figure 6. Lipid droplet size distribution of Lipofundin
MCT/LCT
Lipid Droplets
Figure 6 shows the average lipid droplet size distribution in Lipofundin®
MCT/LCT. It emerges from this curve that the mean particle diameter of
this fat emulsion is about 300 nm, and that more than 99% of all lipid
droplets are smaller than 1 µm.
?-Potential
Emulsion stability is maintained by a negative surface charge exerted
upon each of the lipid droplets. This surface charge of approximately
40 mV is called electrokinetic potential, or ?-potential; prevents
lipid droplets from coalescing on brownian movement collisions; and is
produced by the emulsifier used in manufacturing the emulsion.
The ?-potential may be decreased or neutralized by additives lowering
the pH or containing cations which very rapidly destroy the fat emulsion.
However, if pH is maintained above 5.5-6 and cation concentrations do
not exceed a certain limit (see below), fat-containing PN admixtures may
be stable for several days or even some month. The limiting factor is
nearly always the bivalent cation content (Mg2+, Ca2+)
because the daily dose of these electrolytes in TPN regimens can easily
attain the limit concentration of 6 mmol/L of AIO mixture.
Add Fat Last
Given the above considerations, fat emulsions should always be added
last to an AIO admixture. Premixing all "aqueous" mixture components
results in an acceptable pH range and achieves maximal cation dilution.
Mixing a fat emulsion with glucose solution alone will give an unstable
admixture because the pH of glucose solutions ranges from 3.5-4.5. Premixing
the glucose solution with an amino acid solution will shift the pH to
5.5-6.5, and the fat emulsion can then be added without compromising total
admixture stability.
Lipofundin® MCT/LCT in AIO mixtures
The choice of fat emulsion also has an impact on TPN admixture stability.
As well as offering physiologic advantages, Lipofundin®
MCT/LCT (Medialipide®, Vasolipid®) show
significantly better stability in AIO mixtures than do LCT emulsions.
Müller and Heinemann (10) evaluated various TPN regimens containing
either a pure LCT fat emulsion or a MCT/LCT emulsion. Physical stability
was determined by light microscopy, photon correlation spectroscopy, and
Coulter counter.
The TPN regimens with Lipofundin® MCT/LCT were stable
for at least 7 days. The LCT emulsion containing regimens showed pronounced
creaming. This creamy layer proved hard to disperse. The stability of
these mixed infusions therfore had to be limited to two days. The authors
summed up their findings as follows: "The shelf-life of the mixed
regimens studied by us can be extended from 2 to 7 days if the LCT emulsion
is replaced with Lipofundin® MCT/LCT."
Messerschmidt (9), too, studied mixed regimens and found macroscopic
and microscopic differences as a function of fat emulsion type. After
5 days' storage, LCT emulsions showed significant evidence of creaming
with a 2 to 20 mm thick zone and significant accumulation of large fat
droplets measuring up to 20 µm across (Figure 7).
After replacing the LCT emulsion with a MCT/LCT emulsion in the mixed
regimens, even the upper layer contained no fat droplets > 4 µm
(Figure 1). Brownian movement was clearly recognizable in the MCT/LCT
regimens, but not in the LCT regimens because the droplets in the upper
layer were too large. Coulter Multisizer counting confirmed the microscopic
findings.
Messerschmidt concludes that the tested regimens with pure LCT emulsions
have no emulsion stability when stored for 4 days at 4-8 C or at room
temperature for one day. Lipofundin® MCT/LCT containing
mixed regimens, on the other hand, show only slight changes in fat droplet
size and distribution, and are considered stable even when applying more
stringent drug safety standards.
Stability tests for PN admixtures without fat include:
pH-value:
The pH of the mixture (generally similar to the pH of the amino acid
solution used) is measured because of its importance for the solubility
of folic acid and calcium phosphate and because of its influence on
the stability of the fat emulsion.
Change in colour:
The degree of discolouration is limited, as some chemical reactions,
e.g. the Maillard reaction, are accompanied by a yellowish discolouration.
Transmission:
This test allows the early detection of precipitates and is complementary
to the counts of subvisual particles.
Particle counts:
Counts of subvisual particles are a useful method of detecting precipitation
at a very early stage.
Glucose Table of Contents:
Glucose is consumed in the Maillard reaction. As the quantification
of glucose is easy and accurate, glucose Table of Contents can be used
to detect the Maillard reaction.
Ammonium Table of Contents:
Ammonium Table of Contents is measured as it is indicative of amino
acid degradation.
Stability tests for TPN admixtures with fat:
Fat-containing TPN regimens must additionally be evaluated for emulsion
quality by determination of particle size and distribution. Fat emulsions
in admixtures destabilize in the following steps (Figure 8):
Figure 8. Mechanism of fat emulsion destabilization.
Aggregation means a closer packing of the fat droplets as the repulsive
forces are diminished, while retaining sufficient electric charge barrier
to avoid coalescence. Aggregation can be reversed by changing the condition
that caused the aggregation (e.g. increasing pH). As the aggregates formed
have a lower density than the mixture of fluid and non-aggregated droplets,
aggregation results in the formation of a cream layer. This phenomenon,
referred to as creaming, is also reversible by shaking the container.
Coalescence means that the electric charge barrier breaks down and allows
small fat droplets to flow into one another producing larger droplets.
As with the aggregates these larger droplets will float to the surface
and form initially a cream layer, and ultimately visible oil drops or
an oil layer. This phase separation, in contrast to aggregation, is not
reversible and, as larger fat droplets are formed, causes a deteroration
of the fat emulsion quality making it unacceptable for use.
Fat Emulsion Quality Testing
Fat emulsion quality can be checked by light microscopy, Coulter counter
techniques, laser light extinction, etc. (2). The existance of lipid droplets
comprising >0,4% of the total fat present larger than 5 µm in
diameter has been shown to be pharmaceutically unstable, and therefore
should be considered clinically unfit for parenteral administration (2).
The enclosed "Compatible AIO Admixtures" (see appendix) demonstrates
that numerous high-quality clinical nutrition regimens can be assembled
even when applying the most stringent quality criteria. The shelf life
up to some month enables hospital pharmacists to prepare PN admixtures
prior to need.
Pediatric PN is a particular pharmaceutical challenge because of the
exigencies of per-kg dosing and small volume administration. Standard
regimens can rarely be used. Instead, individualized regimens have to
be developed for each patient on a daily basis. Here is an example:
The high calcium and phosphate requirements of infants may easily
cause the solubility limit to be exceeded. A calcium phosphate crystallization
test is therefore indispensable and should be performed at 37°C to
simulate the situation in the inserted catheter.
The high calcium content of pediatric PN solutions can also sometimes
result in fat emulsion incompatibility. In this cases it is necessary
to administer the fat emulsions separately.
The volumes resulting for the individual regimen components are, in clinical
practice, not amenable to administration by the multibottle system.
The following problems are encountered:
Need to accurately dose small volumes.
Very low, variable infusion rates.
High contamination risk due to multiple manipulations.
Cumbersome pump control.
Need to discard infusion bottle residual volumes.
Significant manipulation and monitoring workload for nursing staff.
AIO admixtures are therefore particularly useful in pediatric PN.
Pediatric admixture compounding calls for meticulous use of aseptic technique
and absolute compatibility of admixture components. Special assembling
aids are available.
The Paedifix® N Burette, for instance, has been specifically
designed and developed to facilitate manual filling of pediatric TPN bags.
The four burette supply lines are connected to large infusion bottles,
and the burette is used to dispense the required volumes rapidly and with
good accuracy.
Hospital pharmacies filling a larger number of pediatric PN bags on a
daily basis may speed their AIO admixture compounding operations by the
use of automatic Caretronic® Compounding System.
To avoid microbial contamination, PN admixtures should not be compounded
on the ward. For organizational and pharmaceutical reasons, PN admixture
compounding is best performed in the hospital pharmacy.
A separate cleanroom with sterile directional airflow and a laminar airflow
(LF) cabinet - which can be used for other aseptic work as well - and
a cleanroom changing & cleaning area should be a must in any hospital
pharmacy filling TPN bags (for more details: e.g. USP-General Information).
Store infusion/injectable solutions as well as disposables and TPN bags
in the filling (clean)room. In the changing & cleaning area, remove
infusion solution bottles from original package and disinfect before transferring
them to the cleanroom (airlock).
Preparing the Infusion Solution Bottles
On a bench adjacent to the LF cabinet, put together infusion regimen
components per prescription order and transfer to LF cabinet. Use alcohol
to disinfect rubber stoppers on infusion solution bottles. Snap ampoules
open, and draw Table of Contents into syringes.
Gravity Filling
TPN bag filling by gravity may be adequate for hospital pharmacies compounding
only a few PN admixtures per day.
First, transfer all aqueous components to the bag and add the fat emulsion
(e.g., Lipofundin® MCT/LCT) last. Next, check empty infusion
bottles against prescription order to be absolutely sure you know exactly
what is in the TPN bag. Then write all pertinent information on the label,
and the TPN bag is ready for dispatch.
Automated TPN Bag Filling
Use a vacuum chamber (e.g., Vacufix®) or an automated
TPN bag filling machine (e.g., Caretronic® Compounding
System) to match your growing TPN bag filling needs.
Standardized TPN is the choice for metabolically stable patients. Critically
ill patients with compromised metabolic and organ functions require individual
patient tailored TPN.
AIO admixtures compounded in TPN filling bags significantly enhance both
the efficiency and the safety of the patient tailored parenteral nutrition.
PN admixtures reduce the manipulation and monitoring workload of the
nursing staff, ensure the continuous and simultaneous infusion of all
daily nutrients, and significantly reduce the risk of microbial contamination
compared to the separate bottle system. AIO admixtures give hospital pharmacists
an opportunity to use their professional skills and expertise to provide
top-quality integral PN regimens.
Dirks, I.; Smith F.M.; Furtado, D.; White, S.J.; Gowin, N.N.
Method for testing aseptic technique of intravenous admixture personnal.
Am. J. Hosp. Pharm. 39, 457-459 (1982)
Driscoll, D.F.
Physicochemical assessment of total nutrition admixture stability and
safety: Quantifying the risk.
Nutrition 13, No. 2, 166-167 (1997)
FDA, Safety alert.
Hazards of precipitation associated with parenteral nutrition.
Am. J. Hosp. Pharm. 51, 1427-8 (1994)
Fossum, K.; Kure, R.; Nygaard, K.
Growth of micro-organisms in all-in-one TPN-admixtures containing lipids.
Clin. Nutr. 7, 73-79 (1988)
Gilbert, M.; Gallagher, S.C., Eads, M.; Elmore, M.F.
Microbial growth patterns in a total parenteral nutrition formulation
containing lipid emulsion
JPEN 10, 494-497 (1986)
Jeppsson, R.; Johansson, M.; Teyborn, J.
Bacterial growth properties in refridgerated all-in-one TPN-mixtures.
Clin. Nutr. 6, 25-29 (1987)
Martens, H.J.M.
Stability of vitamins in TPN
Clinical Nutrition 7 (1988) 74, Special Suppl.
USP - General Information
USP - NF 23, Fifth Supplement, 3531-3546
Specific Reference for Lipofundin® MCT/LCT
Messerschmidt, W.
Fettemulsionen in TPN-Regimen. Untersuchungen zur Stabilität.
Krankenhauspharmazie 8, 331-336 (1991)
Müller, R.H. and Heinemann, S
Stability of TPN-regimens based on Lipofundin/Intralipid containing
a high electrolyte load
Archiv der Pharmazie (1991) 324 (9) 694
B. Braun Nutrition's range of All-in-one Admixtures
(Example for TPN admixtures with a minimum shelf life of 30 days)
Archiv der Pharmazie (1991) 324 (9) 694
General information
The standard regimens in this brochure (without the additional electrolytes,
the trace elements and the vitamins) have a minimum shelf life of 90
days (VR 1 and VR 2 of 30 days) at 2 - 8 °C plus 1 day room temperature
(? 25 °C).
After adding of the additional eletrolytes and/or compatible trace
elements (Tracutil®) and/or compatible vitamin preparations,
the physical/chemical stability is limited to 6 days at 2 - 8 °C
and 1 day room temperature (? 25 °C).
(Because of the degradation of vitamins during storage, it is recommended
to add the vitamins prior to use).
During filling of the bag, please keep to the following sequence:
amino acids ?
glucose ?
electrolytes (Na+ ?
K+ ?
Phosphate ?
Mg++ ?
Ca++), trace elements ?
fat emulsion.
Peripheral Regimens
Central Line Regimens
Lipofundin® MCT/LCT
Description
Lipofundin® MCT/LCT is a sterile, non-pyrogenic
fat emulsion for intravenous administration.
Composition
1000 ml emulsion contain
Lipofundin®
MCT/LCT 10 %
Lipofundin®
MCT/LCT 20 %
Soybean oil
50.0 g
100.0 g
Medium-chain Triglycerides
50.0 g
100.0 g
Glycerol
25.0 g
25.0 g
Egg yolk phospholipids*
8.0 g
12.0 g
Sodium Oleate, a-Tocopherol*, Water for injections
Megajoules/l
(approx.):
4.43 (1022 kcal)
7.99 (1908 kcal)
Milliosmols/l (approx.):
345
380
pH:
6.5-8.8
6.5-8.5
* The amount of egg yolk phospholipids and a-tocopherol
can vary is some countries. Please refer to the country representative.Soybean
oil is a refined natural product containing neutral triglycerides of predominantly
unsaturated fatty acids.
Medium-chain triglycerides are a mixture of neutral triglycerides
of mainly caprylic (about 60%) and capric acid (about 40%).
Clinical Pharmacology
Lipofundin® MCT/LCT provides a source of energy
and essential (polyunsaturated) fatty acids for the patient requiring
parenteral nutrition.
Medium-chain triglycerides are cleared from the bloodstream
at a faster rate and are oxidised more completely for energy production
than long-chain triglycerides. For that reason they serve as preferential
fuel for the body, especially in conditions where the oxidation of long-chain
triglycerides is impaired due to carnitine deficiency, diminished carnitine
palmitoyl-transferase activity etc.
The polyunsaturated fatty acids, which are only provided
by long-chain triglycerides, prevent the biochemical disorders of essential
fatty acid deficiency (EFAD), and correct the clinical manifestations
of the EFAD syndrome.
Phosphatides as contained in egg yolk phopholipids are
involved in the formation of membrane structures and warrant their fluidity
and biological functions.
Glycerol is metabolised in the body as an energy donor
or is used in the synthesis of body glycogen and fat.
Indications Lipofundin® MCT/LCT is indicated as a source
of calories and essential fatty acids for patients requiring parenteral
nutrition.
Contraindications
The administration of Lipofundin® MCT/LCT is contraindicated
in patients demonstrating disturbances in normal fat metabolism such as
pathologic hyperlipaemia, lipoid nephrosis, or acute pancreatitis if accompanied
by hyperlipaemia. It is further contraindicated in patients with ketoacidosis
or hypoxia, in thromboembolism and in acute shock states.
Precautions for use Caution should be exercised in administering intravenous
fat emulsions in patients with metabolic acidosis, severe liver damage,
pulmonary disease, sepsis, diseases of the reticuloendothelial system,
anaemia or blood coagulation disor-ders or when there is danger of fat
embolism.
Administration of Lipofundin® MCT/LCT should be accompanied
by simultaneous carbohydrate infusions making up to 40 % (at least) of
the total calorie intake. When Lipofundin® MCT/LCT is administered,
the patient's capacity to eliminate the infused fat from the circulation
must be monitored. The lipaemia must clear between daily infusions. Especially
where fat emulsions are administered for extended periods of time, the
patient's haemogram, blood coagulation, liver function and platelet count
should be closely monitored.
Paediatric patients: studies have shown the safety and
effectiveness of Lipofundin® MCT/LCT as part of total parenteral
nutrition in neonates and older children.
Lipofundin® MCT/LCT has been aproved for
usage in this patient population in some countries. Registration procedures
are currently pursued in other countries. As long as approval has not
been obtained in a specific country it is up to the judgement of the responsible
physician whether or not to use Lipofundin® MCT/LCT in
this patient group.
Use in pregnancy and lactation
The safety of Lipofundin® MCT/LCT during pregnancy and
lactation has not been assessed, but its use during these periods is not
considered to constitute a hazard. Nevertheless, medicines should not
be used in pregnancy, especially during the first trimester, unless the
expected benefit is thought to outweigh any possible risk to the foetus.
Interactions As a general rule, fat emulsions should not be mixed with
electrolytes, drugs or any other additives in the infusion bottle. Lipofundin®
MCT/LCT may be used with nutrient mixing bag systems only if such resultant
mixtures are compatible and stable.
Special warnings The too rapid infusion of fat emulsions can cause fluid and/or
fat overloading resulting in dilution of serum electrolyte concentrations,
overhydration, congested states, pulmonary oedema, impaired pulmonary
diffusion capacity.
A too rapid infusion of Lipofundin® MCT/LCT can also
cause hyperketonaemia and/or metabolic acidosis, especially when carbohydrates
are not administered simultaneously.
Dosage
1. Adults and school-age children
1-2 g fat per kg body weight and day, corresponding to 10-20 ml of Lipofundin®
MCT/LCT 10 % or 5-10 ml of Lipofundin® MCT/LCT 20 % per
kg body weight and day.
2. Neonates, infants and pre-school children
Neonates
2-3 g (up to 4 g) of fat per kg body weight and day, corresponding to
20-30 ml (up to 40 ml) of Lipofundin® MCT/LCT 10 % or 10-15
ml (up to 20 ml) of Lipofundin® MCT/LCT 20 % per kg body
weight and day.
Especially in preterm infants and low-birth-weight neonates, the ability
to eliminate infused lipids is not yet fully developed. Therefore maximum
fat doses should not be administered to these patients and serum triglyceride
and fatty acid levels should be carefully monitored.
At the end of the daily fat-free interval, the fat must have been cleared
from the serum.
Infants and pre-school children
1-3 g of fat per kg body weight and day, corresponding to 10-30 ml of
Lipofundin® MCT/LCT 10 % or
5-15 ml of Lipofundin® MCT/LCT 20 % per kg body weight
and day.
Infusion rates
In general, fat emulsions should be infused at as low a rate as
possible. During the first 15 minutes the infusion rate should not exceed
0.05 - 0.1 g of fat per kg body weight and hour, corresponding to 0.5-1.0
ml of Lipofundin® MCT/LCT 10 % or 0.25 - 0.5 ml of Lipofundin®
MCT/LCT 20 % per kg body weight and hour. If no adverse reactions are
observed during this initial phase, the infusion rate may be increased
to 0.15 - 0.2 g fat per kg body weight per hour, corresponding to 1.5
- 2.0 ml of Lipofundin® MCT/LCT 10 % or 0.75-1.0 ml of
Lipofundin® MCT/LCT 20 % per kg body weight and hour. The
daily fat infusions should be administered over not less than 16 hours,
preferably as continous infusion over 24 hours.
Method and route of administration Lipofundin® MCT/LCT should be administered
by intravenous infusion as part of a total parenteral nutrition regimen
via a peripheral vein or central venous catheter. Lipofundin®
MCT/LCT can be infused into the same central or peripheral vein as the
carbohydrate and amino acid solutions by means of a short Y-connector
near the infusion site. This allows for mixing of the solutions immediately
before entering the vein. Flow rates for each solution should be controlled
separately by infusion pumps, if these are used.
For safe administration of intravenous fluids from non-collapsible containers
a giving set with a integral airway is recommended.
Overdosage In the event of fat overload during therapy, stop the infusion
of Lipofundin® MCT/LCT, until visual inspection of the
plasma, determination of triglyceride concentrations, or measurement of
plasma light-scattering activity by nephelometry indicate the lipid has
cleared. Re-evaluate the patient and institute appropriate corrective
measures.
Expiry date The product must not be used beyond the expiry date stated
on the label.
Storage Store below 25°C. Protect from freezing. If accidentally
frozen, discard bottle. Unused Table of Contents must be discarded and
should not be stored for later use.
Do not use bottles showing evidence of phase separation.
