Correction of Essential Fatty Acid Deficiency in Newborn Infants by Cutaneous Application of Sunflower-Seed Oil

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ABSTRACT. Two newborn infants receiving long-term, fat free parenteral nutrition developed essential fatty acid (EFA) deficiency. Biochemical evidence of EFA deficiency was documented in plasma, red blood cells, and adipose tissue and included a decrease in arachidonic and linoleic acids, an increase in 5,8,1 l-eicosatrienoic acid, palmitoleic and oleic acids and a trienoic/tetraenoic ratio of more than 0.4. Cutaneous application of sunflower-seed oil, a source rich in the essential fat linoleic acid, rapidly reversed the clinical and biochemical manifestations of deficiency in plasma.

Pediatrics, 58:650-654, 1976, ESSENTIAL FATTY ACID DEFI CIENCY, SUNFLOWER-SEED OIL, NUTRITION.

Certain fatty acids cannot be synthesized by man and must be acquired from the diet. These essential fatty acids (EFA) include linoleic and arachidonic acids, although linoleic acid is readily converted to arachidonic acid in vivo.' Thus, linoleic acid is the primary nutrient necessary for prevention of EFA deficiency. Deficiency of EFA

has been described in infants and children who

have been maintained on fat-free diets2 and fat free intravenous alimentation.@6 Clinical findings in EFA-deficient individuals include dermatitis, thrombocytopenia, increased susceptibility to bacterial infections, and failure to thrive.247

It is possible to provide EFA to deficient individuals with intravenous fat emulsions.4 Although intravenous fat preparations are now available in many countries, including the United States, their infusion is not without complica

tions.5 Press et al.9 recently reported the correc

tion of EFA deficiency in adult man by the

cutaneous application of sunflower-seed oil. We

therefore attempted to correct documented EFA deficiency in two sick newborn infants by the cutaneous application of sunflower-seed oil.

CASEREPORTS*

Case 1

B. H. was a full-term 3,600-gm male infant who required prolonged intravenous alimentation following repair of a large omphalocele. Fluid and calories were maintained solely by the intravenous route for three months. The intravenous solutions included dextrose, electrolytes, vita mins and a parenteral alimentation mixture containing FreAmine II,t but no fatty acids. Fluid intake varied froni 100 to 200 ml/kg/24 hr and calories from 22 to 135/kg/24 hr. During the 11th week on parenteral nutrition the infant developed a generalized scaly eruption which was most obvious over the forehead, face, and the upper anterior chest

(Fig.1).Cutaneous

application

of sunflower-seed

oil was

then begun and continued for three weeks. Improvement and resolution of the skin rash was noted in five days. At 15Â½ weeks of age the infant underwent colostomy, at which time a subcutaneous adipose tissue biopsy was obtained. Healing of the surgical wound was uneventful and the infant is currently gaining weight and doing well on orally adminis tered Portagen@ feedings containing medium-chain triglyc erides.

Case 2

Baby E. was a 32-week 1,800-gm infant who developed severe hyaline membrane disease complicated by a persist ent patent ductus arteriosus and congestive heart failure. At 9 days of age he developed necrotizing enterocolitis for which he received fat-free parenteral alimentation (compo

(Received February 26; revision accepted for publication April 12, 1976.)

ADDRESS FOR REPRINTS: (Z.F.) Department of Pediat rics, Milton S. Hershey Medical Center, Hershey, Pennsyl vania 17033.

Correctionof EssentialFatty Acid Deficiencyin Newborn

Infants by CutaneousApplicationof Sunflower-SeedOil

Zvi Friedman, M.D., F.R.C.P.(C), Stephen J. Shochat, M.D., M. Jeffrey Maisels, M.B., F.A.A.P., Keith H. Marks, M.B., M.R.C.P., F.C.P. (SA), and Edward1. Lamberth, Jr., M.D.

From the Departments of Pediatrics and Surgery, Milton S. Hershey Medical Center, Pennsylvania State University, Hershey, and the Department of Medicine, Vanderbilt University hospital, Nashville, Tennessee

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sition identical to case 1). After 12 days of total parenteral nutrition, cutaneous application of sunflower-seed oil was started and c@@tinued for six days. Following this, oral feedings with breast milk were tolerated and the infant is thriving and d@ing well.

Controls

Three thriving neonates were selected at random from the Newborn Care Unit as controls for lipid analysis of their plasma and erythrocytes. Adipose tissue analysis was performed on

@ 6-day-old infant who died because of severe congenital anomalies.

METHODS

LipidAnalysis

Whole blood, anticoagulated with EDTA, was obtained via a central line or peripheral veni puncture a@i4centrifuged at 0 to 4 C. The RBC

were washed thrice with 0.85% saline. The

plasma and red cells were frozen and stored at

â€”¿50C in 100% nitrogen until lipid extraction was

begun. Adipose tissue samples were weighed

immediately and then frozen similarly prior to analysis. The various lipid fractionsâ€”cholesterol esters, triglycerides, free fatty acids, and phos pholipidsâ€”were separated by thin-layer chroma tography. The fatty acid composition of each lipid fraction was then determined by gas-liquid

chromatography. These methods have been

described previously.'Â° @

@

PI@tletFunÃ tion

Studies

Plateletaggregation was studied using platelet rich plasma prepared as previously described.@ A

Chrono-Log aggregometer (Model S300-1,

Chrono-Log Corp., Broomall, Pennsylvania) was

used for the aggregation studies and adenosine

5'-diphosphate (ADP) (Sigma Chemical Co., St.

Louis, Missouri) and soluble skin collagen (Worth

ington Biochemical Corp., Freehold, New Jersey) were used as the aggregating challenge. Platelet counts on the platelet-rich plasma were done on a Coulter Counte* (Mojel ZBI,

@ Coulter Electron

ics, Hialeah. Florida).

Applicationof Sunflower-Seed

Oil

@ After EF4 deficiency had been confirmed by

plasma lipid analysis, @uÃ±flower-seedoil (fatty

Â°Informed consent for these studies was obtained from the parents of each child and the experimental protocol was approved by the Clinical Investigation Committee of the Milton S. Hershey Medical Center, Pennsylvania State University College of Medicine.

tFreAmine II, McGaw Laboratories, Glendale, California. @Portagen, Mead Joh@ison Laburatories, Evansville, Indi ana.

FIG. 1. Patient 1 showing the skin lesions during essential fatty acid deficiency.

acid composition shown in Table I) was applied to the skin of the trunk and the extremities and rubbed in. Both patients received approximately

1,400 mglkgl24 hr.

RESULTS

PlasmaLipids

Both patients demonstrated EFA deficiency by conventional criteria.1 In addition to severe depletion of linoleic and arachidonic acids there

was a characteristic increase in 5,8,1 1-eicosatrie

noic acid (Table II and Fig. 2). The ratio of 5,8,11-eicosatrienoic acid to arachidonic acid, the â€œ¿trie noic/tetraenoic ratio,â€• is ordinarily less than 0.4.'@ In patient 1, the ratio was 6.3; in patient 2, this ratio was 1.9.

Following treatment, the changes in the fatty acid composition of plasma phospholipids (Table

II and Fig. 2) revealed, as early as five days in case

1 and three days in case2, a dramatic increase in

arachidonate and, in case 2, linoleic acid and a decrease in 5,8,11-eicosatrienoic acid. Changes involving palmitoleic, oleic, and other fatty acids were less consistent.

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Fatty

Acid'%Palmitic8.5Stearic6.6Oleic21.5Linoleic63.0Linolenic0.4

Fatty AcidsÂ°Patient 1Patient 2ControlsDays

After TreatmentDaysAfter

TreatmentBefore

Treatment@â€”&Before Treatment,â€”@---â€˜---â€”-@3 6(No.

3) (Mean Values),_â€”_

.5 13

20C16:032.933.1

32.6 34.133.139.4 36.933.1C16:17.15.2

5.6 6.26.16.0 3.00.5C18:011.111.6

11.9 9.611.05.9 6.311.1C18:lC*)

927.627.9 27.3 26.828.522.7

17.015.7C182w62.41.8

1.6 2.62.95.3 10.312.9C20:3w912.30.1

0.2 0.39.45.8 4.9NDtC20:3w6NDt0.4

0.5 0.5NDt1.0 2.62.6C20:4w62.015.2

16.6 17.14.910.2 15.217.0HFAI4.04.6

3.7 2.73.63.6 3.97.1C20:3w9

R = C20:4w66.3<

0.1 < 0.1 < 0.11.90.8 0.3

TABLE I _was _not _studied) _during _the _EFA _deficiency

state. FATTY ACID CONTENT OF SUNFLOWER-SEED OIL

Adipose tissue

Analysis of case 1 showed a persistently low

linoleic acid after three weeks of treatment. The percent linoleic acid in the adipose tissue triglyc eride was 0.7 versus 8.3 in the control.

During the EFA-deficient state the platelet count in patient 1 was 4.5 X 10@cu mm. Platelet challenge with 2.5@mol of ADP showed impaired aggregation and marked disaggregation, but the response to a challenge with 5.0@imol of ADP and collagen was normal. Following recovery, a chal

lenge with [email protected] of ADP revealed normal

aggregation.

The EFA are necessary for normal membrane

structure and serve as prostaglandin ill .I

Both arachidonate and linoleate are effective in the treatment of EFA deficiency16 but, as linoleic acid is readily converted to arachidonic acid in

Cit;o,1.17 it is the primary nutrient necessary for

the prevention of EFA deficiency. There are two sources of linoleic acidâ€”dietary fat, the prime

Platelet Studies

Â°Most of the lipid content of the oil is present as the triglyceride (triliiiolein) Inoietv.

The fatty acid pattern observed in the RBC phospholipids is less obvious than the pattern seen

in plasma phospholipids except for the low level

Of the linoleic acid and an increased level of

5,8,11-eicosatrienoic acid prior to treatment. Changes that occur in the RBC phospholipids following treatment were less pronounced than the rapid changes of plasma phospholipids.

The pattern of fatty acid changes in plasma and

RBC cholesterol esters, triglycerides, and free

fatty acids was similar to that observed in the phospholipid class before and after the correction of EFA deficiency. No changes in RBC osmotic fragility

@ were detected in patient 1 (patient 2

RBCLipids

DISCUSSION

TABLE II

FAi-rY ACID CONTENT IN PLASMA PHOSPHOLIPID FRACTION OF PATIENTS BEFORE AND AVFER THERAPY AND OF CONTROLS

â€˜¿Palmitic(C16:0), palmitoleic (C16:1), stearic (C18:0), oleic (C18:1 w9), linoleic (C18:2 w6), 5,8,11-eicosatrienoic (C20:3 w9), 8,11,14-eicosatrienoic (C20:3 w6), and arachidonic (C20:4 w6) acids. Abbreviated formula indicates the number of carbon atoms and the number of double bonds. The position of the double bond nearest to the niethvl terminus is indicated by the symbol w

tND = level not detectable.

IHFA = higher fatty acids with carbon numbers >20.

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7

14

21

DAYS

FIG. 2. Percent fatty acid composition in plasma phospholipid fraction of two patients before (0 days) and after therapy with sunflower-seed oil.

source, and adipose tissue stores. In adults there is

enough EFA in such tissue stores to meet the body's requirements for months or even years. In the fetus, however, the proportion of linoleic acid in tissue phospholipids increases with advancing

gestational ageâ€•â€• so that the prematurely born

infant is endowed with limited stores. Because of

their limited nonprotein

caloric reserve, these

infants must mobilize fatty acids for caloric needs when faced with deficient dietary intake. Adipose

tissue triglycerides undergo constant hydrolysis

with the release of EFA and other fatty acids to the plasma. During hyperalimentation, however, the outflow of linoleic acid from adipose tissue is blocked, at least in part, by the high insulin levels accompanying glucose administration.

Prolonged feeding of an EFA-deficient diet has been assoicated with a specific clinical syndrome of dÃ§ficiency in young animals and infants, result ing in a scaly dermatitis (Fig. 1) and failure to develop â€˜¿.â€˜¿Nevertheless, as we have

previously shown,7 very rapid onset of EFA

deficiency can occur in the absence of clinical manifestations. Our second case falls into this Category.

Our two patients showed biochemical and

clinical response to the cutaneous application of

sunflower-seed oil within three to five days. The changes seen in RBC lipids were less pronounced

than those seen in the plasma, perhaps because of the longer time needed for equilibration with the

plasma lipids.2' In spite of changes in RBC

phospholipids, osmotic fragility was not affected, but platelet aggregation revealed the abnormal pattern previously reported.

@ Although there was

rapid correction of the clinical and biochemical

changes of EFA deficiency in patient 1, the

linoleic acid level remained low in the plasma, RBC, and adipose tissue even after three weeks of cutaneous application of sunflower-seed oil. This may be secondary to extreme tissue depletion resulting in a higher requirement of the products of linoleic acid-arachidonic acid and prostaglan dins.

ARTICLES 653

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Absorption of compounds through the skin is well documented in the pediatric literature.21 24 Press et al.@'demonstrated the rapid correction of EFA deficiency in an adult with only 2 to 3 mg of linoleic acid per kilogram per day. This amount is at least ten times lower than previous estimates of

daily requirements of this fatty acid. However, it

seems impossible to predict the exact amount of

lipid that will be absorbed after cutaneous appli cation. Even the relatively large quantities used in our patients (1,400 mglkgl24 hr) failed to replenish tissues deficient in EFA.

The results suggest that cutaneous application of sunflower-seed oil can correct EFA deficiency in sick newborns. However, it is possible that prolonged cutaneous application of linoleic acid may be required to replenish fully depleted fat

stores in severe EFA deficiency. In countries

where intravenous fat preparations are not yet available, or in circumstances where they may be contraindicated, the cutaneous application of a linoleate-rich fat source should be considered. This form of therapy may benefit individuals with chronic fat malabsorption, such as patients with

cystic fibrosis who have been reported to have

defective EFA metabolism.23 It seems likely that those infants who receive diets deficient in EFA but adequate in calories and who are in positive nitrogen balance will benefit the most from this form of therapy. Finally, the ease of application and apparent efficiency of transcutaneous absorp tion of linoleic acid suggest this as a simple and effective prophylactic approach to the preven tion of EFA deficiency in those clinical situations which demand fat-free alimentation.

REFERENCES

1. Holman RT: Essential fatty acid deficiency. In, Holman RT (ed): Progress in the Chemistry of Fats and Other Lipids. Elmsford, New York, Perganion Press Inc, 1968, vol 9, pp 275-348.

2. Hansen AE, Wiese HF, Boelsche AN, et a!: Role of linoleic acid in infant nutrition: Clinical and chem ical study of 428 infants fed on milk mixtures varying in kind and amount of fat. Pediatrics 31:171,

1963.

3. Paulsrud JR, Pensler L, Whitten CF. et al: Essential fatty acid deficiency in infants induced by fat free intravenous feedings. Am J Clin Nutr 25:897, 1972.

4. Caldwell MD, Jonsson HT, Othersen HB Jr: Essential fatty acid deficiency in an infant receiving prolonged parenteral alimentation. J Pediatr 81:984, 1972.

5. White HB Jr. Turner MD, Turner AC, et a!: Blood lipid alterations in infants receiving intravenous fat free alimentation. J Pediatr 83:305, 1973.

6. Pensler L, Whitten C, Paulsrud J, et al: Serum fatty acid changes during fat free intravenous therapy, abstracted. J Pediatr 78:1067, 1971:

7. Adam DJD, Hansen AE, Wiese HF: Essential fatty acids in infant nutrition: II. Effect of linoleic acid on caloric intake. J Nutr 66:555, 1958.

8. Andrew G, Chan G, Schiff D: Lipid nietabolisin in the neonate. J Pediatr 88:279, 1976.

9. Press M, Hartop PJ, Prottey C: Correction of essential fatty acid deficiency in man by the cutaneous application of sunflower-seed oil. Lancet 1:597,

1974.

10. Folch J, Lees M, Sloane-Stanley GH: A simple method for the isolation and purification of total lipids from animal tissues. J Biol Chem 226:497, 1957. 11. Danon A, Heiniberg M, Oates JA: Enrichment of rat

tissue lipids with fatty acids that are prostaglandin precursors. Biochim l3iophys Acta 388:318, 1975. 12. Lamberth EL Jr. Warriner RA,Batchelor ED: Effect of

metabolic acidosi.s and alkalosis on human platelet aggregation induced by epinephrine and ADP. Proc Soc Exp Biol Med 145:743, 1974.

13. Holman RT: The ratio of trienoic-tetraenoic acids in tissue lipids as a nÃ®easureof essential fatty acid requirement. J Nutr 70:405, 1960.

14. Dacie JV, Lewis SM (eds): Practical Hematology, ed 4. New York, Grune & Stratton, 1968, pp 136-141. 15. Samuels.son B: Biosynthesis of prostaglandins. Fed Proc

5:1442,1972.

16. MohrhauerH, Holman RT: The effect of doselevel of

essential fatty acids upon fatty acid composition of the rat liver. J Lipid Res 4:151, 1963.

17. Mead JF: The metabolism of the polyunsaturated fatty acid.s. In, Holman RT (ed): Progress in the Chem istry of Fats and Other Lipids. Ellnsford, New York, Pergamon Press mc, 1968, vol 9, pp 159-192. 18. Roux JF, Takeda Y, Grigorian A: Lipid concentration

and composition in human fetal tissue during devel opment. Pediatrics 48:540, 1971.

19. Bruce A, Svennerholm L: Skeletal muscle lipids. I. Changes in fatty acid composition of lecithin in man during growth. Biochim Biophys Acta 239:393, 1971.

20. Friedman Z, Danon A, Stahlman MT. et al: Rapid onset of essential fatty acid deficiency in the newborn.

Pediatrics 58:640, 1976.

21. Farquhar JW, Ahrens EH Jr: Effect of dietary fats on human erythrocyte f@tttyacid patterns. J Clin Invest 42:675, 1963.

22. Friedman Z, Lamberth EL, Sta@i1man MT. of at: Platelet aggregation in infants with essential fatty acid deficiency, abstracted. International Conference on Prostaglandins, Florence, lt@ly, M@j 26@1975. 23. Feinblatt BI, Aceto T Jr. j3eckhorn G, et a!: Percuta

neous absorption of hydrocortisone in children. Am

J Dis Child 112:@18,1966.

24. Nachman RL, Esterly NB: Increased skin permeability in preterm infants. J Pediatr 79:628, 1971. 25. Rivers JPW, Hassam AG: Defective essential fatty acid

metabolism in cystic fibrosis. Lancet 2:642, 1975.

ACKNOWLEDGMENT

We gratefully acknowledge the editorial assistance of Drs Nicholas M. Nelson and Abraham Rosenberg and the help of the residents and nurses of the Neonatal Intensive Care Unit.

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1976;58;650

Pediatrics

Lamberth, Jr.

Zvi Friedman, Stephen J. Shochat, M. Jeffrey Maisels, Keith H. Marks and Edward L.

Application of Sunflower-Seed Oil

Correction of Essential Fatty Acid Deficiency in Newborn Infants by Cutaneous

Services

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