Effect of Parenteral
Fat Emulsion
on the Pulmonary
and Reticuloendothelia!
Systems
in the Newborn
Infant
Zvi Friedman, M.D., F.R.C.P.(C), Keith H. Marks, MB., M.R.C.P., M. Jeffrey Maisels,
MB., Rebecca Thorson, B.S., and Richard Naeye, M.D.
From the Departments of Pediatrics and Pathology, The Milton S. Hershey Medical Center, Pennsylvania
State University, Hershey
ABSTRACT. Analysis of phospholipids (PL), cholesterol
esters, triglycerides (TG), and free fatty acids (FFA) was performed on plasma and RBCs in two sick low-birth-weight infants who received total parenteral nutrition including Intralipid for the first 9 and 12 weeks of life, respectively.
There was an increase in the total concentration of the
plasma TG and FFA in the infants receiving Intralipid as compared with controls. These elevated lipid levels were not detected by visual inspection of the plasma. When compared
with control infants, higher levels of linoleic acid were found in the plasma and RBCs of infants receiving Intralipid while plasma PL contained less arachidonate. Histological exami-nation of the lung in both infants who received Intralipid revealed numerous globules of sudanophilic material in alveolar macrophages and capillaries. There is a possibility
that prolonged administration of Intralipid may be
asso-ciated with altered pulmonary and reticuloendothelial
system function. Pediatrics 61:694-698, 1978, Intralipid, total
parenteral nutrition, reticuloendothelial system, alveolar
capillaries.
The provision of optimal nutrition for low-birth-weight infants, infants with congenital anomalies of the gastrointestinal tract, and those with inflammatory bowel disease remains a signif-icant problem. Total parenteral nutrition (TPN), which requires the intravenous administration of calories, amino acids, minerals, vitamins, trace elements, and fat, has been established as a form of therapy for these conditions.13
The recent release by the U.S. Food and Drug Administration of an artificial fat emulsion, Intralipid (Vitrum Co., Stockholm), has made available for parenteral feeding a preparation of high caloric density which is rich in essential fatty acids, especially linoleic. However, several hazardous effects of Intralipid in the newborn infant have been reported: a reduced clearance rate in small-for-date infants, as well as among premature infants born before 32 weeks of
gesta-lion and during an acute illness35; displacement of bilirubin from albumin binding sites and an increased risk of kernicterus in jaundiced newborns6; the deposition of lipid material in macrophages which may alter immunity7-8; a potential risk of premature coronary vascular disease9’ 10; the potential risk for substitution of
phytosterols for cholesterol in the developing
CNS, which could lead to changes in myelin
configuration and function; and altered prosta-glandin synthesis rate and turn”
Hyperlipidemia following an infusion of Intra-lipid has been reported to decrease pulmonary
diffusing capacity in healthy adults’2 and to alter
blood flow through the microcirculation.’3
Because of the potential risk involving the use of parenteral fat emulsions in the newborn infant whose respiratory function may already be compromised, we have evaluated two infants who received
TPN
with Intralipid for prolonged pen-cxls, and now wish to present clinical and histo-logical evidence of possible pulmonary and retic-uloendothelial system involvement.STUDY GROUPS
Informed consent for these studies was obtained from the parents of each child and the experimental protocol was approved by the Chin-ical Investigation Committee of the Milton S. Hershey Medical Center, Pennsylvania State University College of Medicine.
Received June 7; revision accepted for publication
September 15, 1977.
ADDRESS FOR REPRINTS: (Z.F.) Department of
Pediat-rics, The Milton S. Hershey Medical Center, Hershey, PA
Patients infusion over 24 hours via a separate infusion set
Case 1. Patient 1 was a 1,280-gm girl born at 30 weeks’
gestation. The infant developed severe hyaline membrane disease and required mechanical ventilation. The clinical course was complicated by pneumothoraces, intracranial
hemorrhage, patent ductus arteriosus and congestive heart failure, necrotizing enterocolitis, chronic bronchopulmonary
dysplasia, and recurrent episodes of pneumonia. From the
fifth day on her condition was maintained solely on
periph-eral TPN. The intravenous solutions included dextrose,
electrolytes, trace elements, and vitamins in addition to a
parenteral alimentation mixture containing Freamine II
(McGaw Laboratories, Glendale, Calif.) and parenteral fat emulsion as 10% Intralipid. Fluid intake varied from 120 to 200 ml/kg/24 hr and calorie intake from 60 to 125/kg/24 hr. Fat in the Intralipid infusion varied from 0.5 to 4.0 gm/kg, 24 hr (total fat, 141.2 gm), depending on the ability of the infant to clear the infused triglycerides as assessed by visual inspection of the plasma. Intralipid infusion was terminated 28 hours before death. At 1#{189}months, she developed chole-static jaundice and died on the 70th day.
Necropsy revealed severe bronchopulmonary dysplasia,
acute focal bronchopneumonia, infarcts of the basal ganglia and the paraventricular regions, acute multifocal myocardial necrosis, peritoneal adhesions, intrahepatic cholestasis, old subarachnoid hemorrhage, and hemosiderosis of the spleen.
Case 2. Patient 2, the second of twins, was born at 31
weeks of gestation weighing 1,200 gm. Examination revealed multiple congenital anomalies: tracheoesophageal fistula, imperforate anus with a fistula to the posterior labia, thoracic hemivertebra and scoliosis, rib anomalies, single ectopic pelvic kidney, and absence of uterus and vagina. On admission, agastrostomy was performed followed by a series of dilatations of the upper esophageal pouch. The infant’s
condition was maintained solely on peripheral TPN. The
intravenous solutions were similar to those described in case
1. Fluid intake varied from 120 to 180 ml/kg/24 hr and
calories from 60 to 155/kg/24 hr. Fat content in the Intralipid infusion varied from 0.5 to 4.0 gm/kg/24 hr (total fat, 184.8 gm). Intralipid infusion was terminated 72 hours before death. At 1 month of age cholestatic jaundice
devel-o_. Repeated episodes of pneumonia complicated the clinical course, and during the tenth week disseminated intravascular coagulation developed. In spite of vigorous
therapy, she died on the 83rd day.
Necropsy revealed the previously mentioned congenital anomalies; disseminated fungal microabscesses in the heart, lungs, kidneys, and the thyroid; cortical infarcts in the
kidneys; severe cholestasis; diffuse hemorrhages including massive ones in the upper part of the gastrointestinal tract; subendocardial hemorrhage of the left ventricle; and recent
frontoparietal subdural hematoma.
Controls
Two thriving premature infants who were receiving Similac (Ross Laboratories, Columbus, Ohio) were studied as controls. Their gestational ages were 26 and 28 weeks and their birth weights were 840 and 1,120 gm, respectively. At the time of the study, they were 24 and 33 days old and their weights were 1,160 and 1,600 gm,
respec-tively.
METHODS
Ten percent Intrahipid was given as a constant
which joined the glucose and amino acid mixture at a three-way tap connector just distal to the venous cannula. Both solutions were changed
daily and infused with mechanical pumps. The
initial Intralipid dose was calculated as 0.5 to 1.0
gm/kg/24
hr and was increased by approximately 1.0 gm/kg every 24 hours up to a maximal quantity of 4.0 gm/kg/24 hr. Visual inspection of the plasma for hyperlipidemia was obtained every six hours by centrifugation of a blood-filled hepa-rinized capillary tube (50 tl). The rate of the Intrahipid infusion was adjusted according to the ability of the infant to maintain plasma that was clear to visual inspection.Upid Analysis
Whole blood with ethylenediaminetetraacetic
acid as anticoagulant was obtained via a central
line
or peripheral venipuncture and centrifuged at 4 C. The plasma and RBCs were frozen and stored in 100% nitrogen until lipid extraction was begun. The various lipid fractions-phospholipids(PL),
cholesterol esters (CE), triglycerides (TG), and free fatty acids (FFA)-were separated by thin-layer chromatography, and the fatty acid composition of each lipid fraction was then deter-mined by gas-liquid chromatography.’ The age of the patients at the time of sampling is shown in Tables I and II.RESULTS
The fatty acid content of plasma PL, CE, TG, and FFA in the two patients and controls is shown in Table I. An increase in the total content of the plasma TG and FFA was found in the infants who received Intrahipid as compared with controls.
Also,
an
elevated level of hinoleic acid (cl8:2 w6)
in plasma PL, CE, TG, and FFA and a decreased level of arachidonate (c20:4 w 6) in plasma PL were noted in the two patients as compared with controls. The fatty acid content of the RBC PL showed elevated levels of linoleic acid in the patients after administration of Intrahipid as compared with controls (Table II).
Frozen sections of the lungs stained with Oil Red 0 revealed diffuse deposition of fat globules in alveolar macrophages and capillaries in both patients (Figure). Deposition of fat globules was also seen in liver Kupifer cells. Oil Red 0 stains a wide variety of lipids and is particularly effective in staining neutral fats.
DISCUSSION
TABLE I TABLE II
PERCENT FArI-Y ACID CONTENT OF PLASMA LIPIDS IN PATIENTS TREATED WITH INTRALIPID AND IN Corn-noLs
Fatty Acids0 Patient 1
(Methyl Esters) 64 Dayst
Pat 60 ient 2
-82 ControLs (No. = 2),
Mean
Dayst Dayst
Phospholipids
clB:0 32.1 30.7 29.7 32.7
c18:0 13.3 14.7 13.8 15.1
cl8:1 w9 20.6 21.0 13.5 16.4
c18:2w6 26.0 25.0 30.2 17.6
c20:4w6 4.0 4.1 5.4 7.4
c22:6W3 3.0 3.7 1.2 1.2
Total mg/mi 1.63 1.56 1.43 1.47
Cholesterol esters
c18:2w6 46.8 . . . 51.0 29.3
cZO:4w6 3.8 .. . 3.5 2.2
Total mg/mi 0.62 . .. 0.65 0.52
Triglycerides
cl8:2w6 47.4 39.8 44.0 28.2
Total mg/mi 1.19 1.55 1.98 0.38
Free fatty acids
c18:2w6 32.6 19.7 25.0 11.9
c20:4 w8 8.6 8.7 6.4 3.4
Total mg/mi 0.18 0.22 0.29 012
#{176}Paimitic (c16:0), palmitoleic (c16:l), stearic (c18:0), oleic (c18:1 w9), linoleic (c18:2 w6), dihomo-’y-linolenic (c20:3C0 6), arachidonic (c20:4 w6), docosahexaenoic
(c22:6 ‘o3). Abbreviated formula indicates the number of
carbon atoms and the number of double bonds. The position
of the double bond nearest to the methyl terminus is
indicated by the symbol o. tAge when treated.
the newborn infant it is difficult to provide an
optimal caloric intake in the form of amino acids and carbohydrates because excessive fluid volumes are needed when isotonic solutions are used, and the glucose load of hypertonic solutions is frequently not tolerated. Therefore, fat emul-sions, which have a high caloric density and low
osmolality, have been used increasingly to
provide additional calories and essential fatty acids. Intralipid, like most vegetable oils, is rich in the essential fat linoleic acid, which accounts for
509o of its fatty acid content. The present study clearly demonstrates, as have others,15”6 that the administration of a fat rich in linoleic acid results
in an increase of the hinoleic acid level in the plasma, with a concomitant decrease in the arachidonic acid level.
Intrahipid is cleared from the bloodstream by a
mechanism similar to that of natural
chylomi-crons requiring the enzyme lipoprotein lipase.’7 Several methods are used to monitor the plasma TG levels, including visualization for lactes-cence,’8 nephelometry,4 and chemical
determina-PERCENT FATTY ACID CONTENT OF ERYTHROCYTES IN
PATIENTS TREATED WITH INTRALIPID AND IN Cor’’rnoLs
Fatty Acids0 Patient 1
64 Dayst
Patient 2
r-ControLs (No. = 2),
60 82 Mean
Dayst Dayst
Phospholipids
c16:0 28.5 24.5 29.3 31.7
c18:0 12.6 11.6 12.6 12.1
c18:1o9 21.8 18.6 18.7 31.2
c18:2w6 209 23.3 22.9 9.3
c20:4#{248}6 8.8 12.0 12.6 12.6
#{176}SeeTable I for explanation of abbreviated formulas.
tAge when treated.
lion. It is important to realize the discrepancy between the increased TG blood level as deter-mined by gas-liquid chromatography and the apparent “clear plasma” by visual inspection. The increased TG and FFA content of the plasma during the administration of Intralipid to low-birth-weight infants has been noted by others.3’5”9
Both patients developed cholestatic jaundice after having received TPN for foui to six weeks. This has been previously described in association with the administration of TPN.2#{176}Whether the liver dysfunction was a contributing factor in the development of hyperlipidemia in these sick infants or whether Intrahipid contributes to the cholestasis is not clear.
The role of the lung and tissues other than fat, liver, and muscle in removing chylomicrons from the peripheral circulation has been demonstrated in the rat,21’22 but the rate at which the reticuloen-dothelial system clears the blood of chylomicrons
is in dispute. Waddell et al., by blocking the
reticuloendothehial system, did not significantly
alter the rate of clearance of chylomicrons.23 However, other experiments have shown that the administration of intravenous fat emulsions results in the accumulation of pigmented fatty material in the reticuloendothehial system and its deposition is related to the amount and the duration of the Intrahipid infused.24’25 One of our patients received 1,412 ml of Intralipid in 65 days, and the other 1,848 ml in 72 days. Both demonstrated diffuse deposition of fatty material in the alveolar macrophages. Similar
findings
?*_,y
+
‘_4
Left and right, Photomicrographs of lung, showing diffuse deposition of fat globules in alveolar macrophages and capillaries (arrows) (Oil Red 0, original magnification x900 on left, original magnification X 1,280 on right).
which are taken up by the macrophages.2 These cells are an integral part of the
reticuloendothe-hal system and play an important role in the host
resistance to bacterial, viral, and fungal infec-tions. 2fi. 27 It has been demonstrated that the
administration of fat emulsions into animals can
block the reticuloendothelial system, a process that results in depressed resistance to infection.28
Both patients had recurrent episodes of
pneu-monia and one infant died of fulminant fungal
septicemia. Thus, it is possible that the prolonged Intralipid infusion contributed to their morbidity
by altering their host resistance.
A transient decrease in pulmonary diffusing capacity has been reported in normal adults following a four-hour infusion of Intralipid, and
the degree of involvement was correlated with
the level of hyperlipidemia.’2 Our patients
demonstrated pulmonary involvement; one had
hyaline membrane disease complicated by
chronic bronchopulmonary dysplasia, patent
duc-tus arteriosus with a large left to right shunt, and
recurrent episodes of bronchopneumonia, and the
second patient had a tracheoesophageal fistula
and recurrent episodes of pneumonia. Since
adults with normal basal pulmonary function who
received parenteral fats were transiently affected
by the short-lived hyperlipidemia,’2 it seems reasonable to postulate that chronic hyperlipi-demia was present in our patients and could have had a deleterious effect on the already compro-mised pulmonary performance.
Several investigators have postulated that
lipid-induced changes in gas exchange may result from
an alteration in the erythrocytes. Greene et al.
observed erythrocytes in the rabbit lung to be
coated with lipid particles.12 We observed numerous fatty globules in alveolar capillaries that could have adhered to RBCs or changed their investment. Our findings (Table II) and those of
othersl516 demonstrate the alteration in RBC fatty
acid composition during changes in dietary fat intake. These changes may affect the biophysical
properties of the RBC membrane and thus alter
gas
exchange. Hyperlipidemia may cause themature erythrocyte to lose membrane cholesterol
reversibly by donating it to circulating
chylomi-crons and very-low-density lipoproteins. These
changes may decrease the RBC surface area and
proportionately increase its volume.#{176}3’ Lipid-induced changes in the RBC may also lead to an
increase in blood viscosity and diminished flow.
Several authors have reported increased RBC adhesiveness and aggregation associated with hyperlipemia which, in turn, may alter small
vessel and capillary flow.3233 This phenomenon is
minimal with 10% Intralipid.3
The administration of parenteral fat emulsion is widely used as an integral part of therapy with
TPN. However, in patients with compromised
pulmonary function and reduced host resistance,
particularly in sick low-birth-weight infants, this
therapy may increase morbidity by further
altera-tion of pulmonary function and resistance to
infections. Moreover, in these instances even
close monitoring of plasma chylomicrons with conventional methods might not prevent hyper-lipidemia. Therefore, Intralipid should be used in these patients with extreme caution. In both published35 and unpublished data (Z. Friedman),
it has been shown that in those circumstances in
adequate calories can be furnished by carbohy-drate and protein, supplementation of essential
fatty acids can be achieved by inunction with
vegetable oil.
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ACKNOWLEDGMENT
We gratefully acknowledge the editorial assistance of Drs.
Nicholas M. Nelson and Abraham Rosenberg and the help of
