Lipid Emulsions:
Dosage and Monitoring
Olivier Goulet, M.D.
Gastroentérologie et Nutrition, Hôpital Necker-Enfants Malades, 75743 Paris cedex 15, France
phone +33-1-4449-4412, fax +33-1-4449-2501, email: olivier.goulet@nck.ap-hop-paris.fr
Learning Objectives
 To understand the optimal glucose / fat ratio
 To be familiar with methods for adequate assessment of the intravenous lipid
clearance and tolerance
 To identify the mechanisms of lipid overload and the patients at risk
 To understand possible relation between long-term fat infusion and liver disease
Introduction
After a period of development of the technique and of improvement in prevention of complications, parenteral nutrition (PN) is now widely used in a variety of indications in adult
as well as in pediatric patients. Macro- and micronutrients given exclusively through the
central vein for prolonged periods are sufficient for nutritional recovery and maintenance
as well as growth in children.
One of the current objectives is to adapt the PN intakes to the clinical and nutritional
situation. Indeed, it is essential that the composition of the intravenous feeding solution be
adjusted according to age and disease, to the clinical and biological criteria and as a
function of the progressive transition from parenteral to enteral feeding.
Energy intake is closely correlated with that of nitrogen (nitrogen/energy ratio). Glucose is
the unique carbohydrate used during TPN. The use of other carbohydrates (fructose) is
not advised. The infusion rate of glucose must be kept constant without exceeding rate of
1 g/kg per hour or 1.5 g/kg per hour especially in infants and children. Under these conditions the appearance of a glucosuria indicates a technical problem with the infusion rate
or some metabolic disorder, especially during sepsis or any situation of stress. Intravenous fat emulsions (IVFE) are usually added to the PN regimen because they provide
essential fatty acids and a concentrated source of calories with a relatively low osmotic
load. IVFE enables the physician to provide a highly concentrated source: 2.2 kcal/ml for
the 20% emulsion, compared to 0.68 kcal/ml for a 20% dextrose solution. The concentrated calories and low osmolality of IVFE make it ideal for peripheral parenteral nutrition. The
use of IVFE also allows the energy input to be diversified, with a reduction in the
consequences of excessive glucose supply. In addition it was well demonstrated in adults
as well as in pediatric patients that the use of IVFE improves net nitrogen balance [1-4].
Optimal Glucose : Fat Ratio
In the past, TPN for adults, children and infants provided most of the energy as glucose,
although it was not precisely known how much of the iv-administered glucose was oxidized. Glucose-based TPN has been shown to cause adverse effects related to glucose
storage, particularly as fat. This might account for the extensive lipid deposition reported
both in liver and adipose tissue [5-6]. In these conditions, fat infusion further increases fat
deposition and may result in fat overloading. Thus, substitution of part of the glucose
calories avoids the undesirable effects reported with glucose-based TPN. Recent studies
performed in infants or neonates have assessed glucose and fat utilization [7]. By using
five isocaloric TPN regimes differing in their glucose/lipid ratio, it was possible to assess
for the optimal glucose infusion rate [7]. Fat infusion aiming at a significant contribution to
the coverage of energy expenditure requires that glucose oxidation be equal to or lower
than maximal oxidative glucose disposal.
A study in malnourished infants and young children has shown that the amount of infused
lipid must be adapted to lipid oxidation capacity [8]. There is a maximal lipid utilization rate
of about 3.3 to 3.6 g/kg/day (infants). Pierro showed similar results in a short-term study
performed in surgical neonates on TPN [9].
Finally, short-term as well as long-term lipid use must be included in all TPN programs in
infants, children and adults.
Assessment of Lipid Clearance
The composition of IVFE results in a mixture of artificial chylomicrons having physicochemical characteristics very similar to those of the natural chylomicrons produced by
enterocytes. They are hydrolysed by lipoprotein lipase (LPL) in capillaries of adipose
tissue and muscle. This step determines the rate at which fatty acids from the emulsion
are transported into the tissue for storage or oxidation. Like many other key enzymes, LPL
can be regulated both in amount and in activity. The amount of LPL at the capillary
endothelium is under hormonal control, while its activity is regulated by the specific activator apo CII [10].
Lipid clearance test have been developed in the past but are not used routinely in clinical
practice. They allow understanding of the factors determining the elimination of exogenous fat emulsions from the circulation [11]. An intravenous fat tolerance test using Intralipid was developed in the late 1960s demonstrating that the emulsion was handled in a
similar manner to that of endogenous chylomicrons. Patients with moderate trauma, for
example after cholecystectomy, have an increased fractional elimination rate in comparison with healthy controls. Critically ill patients on the other hand have an elimination rate
which is lower or close to that of healthy controls [12].
Lipids being not water-soluble have to be transported bound to proteins. The lipoproteins
play a key regulatory role in the metabolism and elimination of exogenous lipids. The endogenous VLDL particles undergo degradation to LDL in plasma under the action of LPL.
These particles contain apoCII which acts as an activator of LPL. Exogenous TG particles
are handled in the same way but have to acquire apo CII mainly from the HDL fraction
before they can be hydrolyzed. During the degradation of VLDL particles there is a continuous exchange of apolipoproteins and surface material. Apo C, apo E and phospholipids
are removed during lipolysis and transferred to HDL. As donor of apo CII and acceptor of
abundant surface material, HDL play a key regulatory role in the metabolism of VLDL and
exogenous lipids. As might be expected, the serum HDL concentration is positively correlated to the fractional elimination rate of exogenous fat emulsions. HDL-cholesterol has
been shown to be low in critically ill patients as well as Apolipoprotein CII. The low HDL
and impaired apolipoprotein pattern taken together is a possible explanation for the disturbance in the elimination capacity of exogenous lipids seen in some critically ill patients.
Patients treated with heparin due to deep vein thrombosis have been studied using the
intravenous fat tolerance test. The fractional elimination rate decreased during heparin
treatment and after interruption of heparin infusion the elimination rate slowly returned to
normal. Heparin acts by activating and releasing LPL from the endothelial surface and
when given together with exogenous fat emulsions causes a sharp increase in circulating
LPL activity and FFA levels. Sometimes this might be a positive effect, but in patients with
already high FFA levels an increase in lipolysis may lead to extremely high FFA values.
Heparin is necessary for clinical reasons in many situations and it would be an advantage
if the increase in lipolytic activity could be avoided. Low molecular heparin is an interesting
alternative in these situations, since its effect on lipolysis is much less than that of
unfractionated heparin. There is no place for routine administration of heparin together
with the fat emulsion as proposed in the past.
Metabolic monitoring of patients prior to and during infusion of IVFE should include
 fasting plasma triglycerides (TG)
 total cholesterol
 plasma LDL- and HDL-cholesterol.
Normal plasma TG levels do not mean that exogenous triglycerides are adequately used
(oxidation) or stored (adipose tissue). Indeed, part of the exogenous lipids may be cleared
by other mechanisms, especially removal by the reticuloendothelial system (RES). High
plasma TG levels, however, suggest impaired clearance related to excessive infusion rate
and/or decreased LPL activity.
There may also be several classical contraindications to the use of IVFE during the initial
phase, such as sepsis, thrombocytopenia, disseminated intravascular coagulation, respiratory distress syndrome or metabolic acidosis. Furthermore, administration of IVFE during neonatal jaundice has to be careful as there is a risk of displacing non-conjugated
bilirubin from albumin with free fatty acids.
Fat Overload and Liver Disease
The fat overload syndrome (FOS) has been reported a long time ago and was thought to
be related to the captation of exogenous particles by the reticuloendothelial system (RES)
[13]. Its acute clinical and biological expression was described as mimicking septic syndrome but related to macrophage activation. Symptoms include high fever, hepato-splenomegaly, jaundice, respiratory distress syndrome, bleeding, thrombocytopenia, disseminated intravascular coagulation, metabolic acidosis, and hypoalbuminemia [14]. Cessation
of lipid administration most of the time is insufficient for improving the patient’s condition.
Steroids have been shown to stop the process of macrophage activation.
More recently we have reported several cases of severe cholestasis supposed to be related to long-term administration of IV lipid [15]. Liver disease is a major side-effect of
long-term PN. Fifteen years after the first reports its pathogenesis is not completely understood [16]. Disruption of th enterohepatic circulation of bile acids in case of ileal resection, impairment of choleresis in the absence of oral feeding, bacterial overgrowth due
to bowel obstruction, stasis and loss of the ileocaecal valve are patient-dependent factors
thought to contribute to PN-associated cholestasis [17]. One mechanism might be an increase in bile concentration of lithocholic acid [18]. Bacterial infections were also proposed as a co-factor in PN-related cholestasis, since the sepsis-associated cholestasis
has been well described, both in human and animal models [19-21]. Duration of PN is
also a known risk factor. Qualitative aspects of PN are also a matter of debate. Experimental evidence suggested that an excess in total energy delivered induces liver lesions,
reversible when decreasing the energy supply [22]. The role of amino acids was suspected, either excess or lack of them [23,24] , and an excessive glucose supply might
induce steatosis through the increase in de novo lipogenesis [25].
Although lipids are necessary in patients on PN, they are strongly suspected to be toxic in
some cases. The metabolism of their oxidized fraction is relatively well known, far less the
destiny of the non oxidized fraction, which is caught by the reticulo-endothelial system in
the liver and also by the spleen, bone marrow and lungs. Chronic administration of lipid
emulsions might overload reticuloendothelial cells and induce their acute or chronic activation. It must be noticed though that an excess of liver macrophages and portal infiltration with eosinophils has been previously described in PN-dependent patients, but not
attributed to lipid toxicity [26]. Accumulation of exogenous lipids in the liver Kupffer cells
may also impair the clearance of endotoxins and increase their deleterious effect on the
liver. Moreover, the peroxidation of exogenous lipid could produce toxic metabolites despite the simultaneous infusion of vitamin E [27]. Phytosterols contained in lipid emulsions
may also have a deleterious effect on biliary secretion [28].
From our recent study, several arguments are in favour of a toxic role of parenteral lipids
for the liver. First, it was observed that several episodes of cholestasis occurred after a
recent change in the mode of lipid delivery. Second, hematologic disorders compatible
with a macrophage fat overload occurred in several cases contemporary to the onset of
cholestasis and frequently improved together with cholestasis after suspension or decrease in lipid infusions.
Withholding lipid emulsions from PN-dependent patients is not free from risk. As expected, prolonged lipid withholding induced growth retardation in childhood and essential fatty
acid deficiency. The increase in daily glucose supply is not a satisfactory prevention of
failure to thrive, because of the induced insulin resistance [29], and the risk of subsequent
liver steatosis.
Lipid-induced complications have to be taken into account in the decision for small bowel
transplantation (SBT) in children with irreversible digestive disease [30]. Failure to thrive
secondary to repeated or prolonged lipid suspension might be an indication for isolated
SBT, before the development of severe liver disease. The liver status should be checked
regularly by plasma liver tests and liver biopsies in patients on waiting list for isolated SBT,
especially in case of mild liver fibrosis at the time of decision for isolated SBT. We have
recently showed in a group of children on total PN that severe liver fibrosis may appear
over the first 4 years of life and then rapidly progress from septal fibrosis to cirrhosis [31].
Patients who are sensitive to lipid toxicity might be at risk for rapid course of liver fibrosis.
Taking into account the waiting delay for transplantation, one could suggest to plan rapidly
combined transplantation in children presenting with lipid intolerance and severe liver
fibrosis.
Rules of lipid administration in PN-dependent children may be proposed:
 maximal daily amount of 2 to 2.5 g/kg/d
 maximal infusion rate of 150 mg/kg/hour
 no more than 5 lipid infusions weekly
 maximal lipid-to-energy ratio of 25%.
In children receiving lipid emulsions, liver tests and platelet count should be monitored
regularly.
When cholestasis occurs, biliary obstruction, infection or drug toxicity should be ruled out
by appropriate investigations. Platelet count <150.000/mm 3 associated with an increase in
plasma transaminases, a fortiori an increase in plasma bilirubin, is strongly suggestive of
lipid toxicity when all other explainations are ruled out. Bone marrow aspiration, liver biopsy and temporary cessation or decrease in lipid infusion should be discussed. Lipid
infusion should be stopped until normalization of bilirubin level and platelet counts. Essential fatty acid deficiency has to be carefully checked.
Medium-chain based emulsions (50% MCT) might help to minimize the LCT load and
theoretically their hepatic deposition [32-34] and long-term toxicity, but neither the current
study nor other clinical data have demonstrated any effects of MCT- based emulsions to
prevent or to reverse long term PN-associated cholestasis or hematologic complications
[35-38]. Emulsions based on olive oil might also reduce the risk of lipid toxicity due to
peroxydation, by decreasing the amount of linoleic acid [39,40].
Finally there is a relationship between lipid emulsions, macrophage activation syndrome,
thrombocytopenia and cholestasis in a pediatric population homogeneous for liver disease
risk factors. As lipids are indispensable in PN-dependent children, we recommend
prevention through limitation of lipid supply and infusion rhythm to the patient's theoretical
oxidizing capacity. The preventive role of long term use of emulsions countaining low
proportion of polyunsaturated fatty acids needs to be explored in further studies.
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