Vitamin E—How Much Is Too Much?

COMMENTARIES 625 inadequate by current investigational standards.

Another pitfall to be avoided is that of being so enamored of our own favorite theory or therapy that we fail to consider other approaches,

exempli-fled

efficacy of stimulant therapy. Clearly, like the ex-cellent clinician he obviously is, he recognized the

importance of other management techniques and:

“used environmental manipulation, social and to-ken reinforcement, reward, punishment, extinction, and time out.” Yet, despite this and other evidence that a variety of management procedures were em-ployed, Eichlseder attributes his success to phar-macotherapy, when, in reality, his approach prob-ably more accurately represents a pediatric equiv-alent of what Satterfield and Satterfield’ have termed “multimodality therapy.”

Finally, the clinician investigator should inves-tigate only what is reasonable within the context of

his or her own practice. Such a recommendation

seems self-evident but would preclude a great deal of time and energy being expended on projects that

can only be accomplished within the framework of

a large multidisciplinary study. For example, long-term follow-up of children with attention deficit

disorder demands resources beyond what an

mdi-vidual practitioner can devote to studies of this

kind. Studies such as those of Weiss and her

associates2 require personnel to locate and then contact each subject and contrast with the well-intentioned but apparently inadequate follow-up described by Dr Eichlseder.

We believe it is possible for the practicing pedia-trician to engage in the kind of clinical research

studies described by Dr Eichlseder. However, if he

or she is to make a significant contribution, the clinician investigator must incorporate into the study design the methodology of state-of-the-art clinical research.

REFERENCES

SALLY E. SHAYWITZ, MD

BENNETT A. SHAYWITZ, MD

Departments of Pediatrics, Neurology, and the Yale Child Study Center Yale University School of Medicine New Haven, Connecticut

1. Satterfield JH, Satterfield BT, Cantwell DP: Three-year multimodality treatment study of 100 hyperactive boys. J Pediatr 1981;98:650-655

2. Weiss G, Hechtman L, Milroy T, Penman T: Psychiatric status of hyperactives as adults: A controlled prospective 15-year follow-up of 63 hyperactive children. J Child Psy-chiatry 1985;24:211-220

Vitamin

E-How

Much

Is Too

Much?

For many years a treatment in search of a disease, vitamin E (a-tocopherol) is now being prescribed widely and in large doses to small premature in-fants. The possibility of reducing the incidence of severe retrolental fibroplasia,’ intraventricular hemorrhage, and even the mortality of these tiny babies5 has, quite understandably, excited the in-terest of those responsible for their care.

Although concern about potential toxicity has been expressed,6’7 Hittner and co-workers4

recom-mend that infants weighing less than 1,500 g at

birth who require oxygen receive intramuscular in-jections of a water miscible preparation of d,l-a-tocopherol on days 1, 2, 4, and 6 of life as well as oral a-tocopherol in a dosage of 100 mg/kg/d.5 Using this regimen, these workers report that they have not (or have rarely) encountered plasma to-copherol levels in excess of 3.5 mg/dL.8’9 This has not been our experience, however, and if plasma levels are indeed related to vitamin E toxicity, the widespread use of relatively high doses of vitamin E (in the absence of rigorous control of plasma levels) could be hazardous.

Our experience with the use of oral vitamin E

indicates that serum levels are frequently elevated to potentially toxic levels on recommended dosages.

At the James Whitcomb Riley Hospital for

Chil-dren 78 infants weighing less than 1,500 g at birth received 100 mg/kg/d of Aquasol E (divided into four doses) from day 1 of life and were followed with weekly or semiweekly plasma determinations

during a 6-month period. In the 78 infants, 557

plasma vitamin E levels were measured. No

intra-venous vitamin E was administered within seven

days of any vitamin E level. Elevated plasma

con-centrations were very common (Table). Of the 557 levels obtained during vitamin E supplementation,

211 (38%) were greater than 3.5 mg/dL, whereas 72

(13%) exceeded 5.5 mg/dL. Although oral

supple-mentation was discontinued when the level

ex-ceeded 3.5 mg/dL, concentrations often remained above 3.5 mg/dL for several days or exceeded 3.5

mg/dL again when Aquasol E supplementation was

reinstituted at a reduced dosage of 25 or 50 mg/kg/ d. Because of similar experience at the Hershey Medical Center, the daily dosage was reduced to 50 mg/kg/d.

To discuss the potential adverse effects of

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No.

4 October

1985

TABLE. Distribution Measured in 78 Infa 1,500 Grams

of 622 Serum T nts with Birth W

ocopherol Levels eights of 500 to

Tocopherol Level (mg/dL)

No. of Levels % of Total No. 0-0.4 0.5-1.4 1.5-2.4 2.5-3.4 3.5-4.4 4.5-5.4 5.5-8.0 8.0 3 72 131 140 96 43 57 15 0.5 12.9 23.5 25.1 17.3 7.7 10.3 2.7

vated plasma concentrations of a-tocopherol, a

brief review of tocopherol metabolism may be use-ful. There are at least eight different naturally occurring tocopherols with antioxidant activity,’0 of which a-tocopherol (the free alcohol form) is the most important, constituting more than 90% of the

tocopherol present in animal tissues. Vitamin E

activity, however, is standardized against d,l-a-to-copherol acetate, an acetate ester which, by defini-tion, contains one unit of vitamin E activity per milligram. a-Tocopherol acetate (the active ingre-dient in Aquasol-E [USV Laboratories]) is hydro-lyzed to a-tocopherol in the gastrointestinal tract prior to absorption into the blood stream. After intravenous administration to newborn rabbits on day 1 of life, hydrolysis of the acetate form occurs slowly if at all.” However, the ability of the human preterm infant to convert the acetate to the free form after parenteral administration has not been studied thoroughly to our knowledge.

In addition to the a form, other isomers of to-copherol exist (i3, ‘5,‘) that possess varying degrees of vitamin E activity. They are normally present in

low concentrations in human milk and formulas

and, therefore, may be disregarded for most clinical purposes, particularly if our concern is excessive

plasma levels. However, accurate measurement of

specific isomers of tocopherol may be necessary

when we are attempting to diagnose vitamin E

deficiency. Methods commonly utilized to measure plasma and tissue tocopherol levels include high pressure liquid chromatography (a technique able to separate the isomers) and a fluorescence method

described by Hansen and Warwick.’2 The latter

assay quantifies the total, free, and acetate forms of tocopherol but cannot differentiate the isomeric forms.

We do not have extensive data about the phar-macokinetics of tocopherol in the low-birth-weight infant, but reports indicate that intestinal absorp-tion is variable and may depend upon gestational age, postnatal age, relative fat absorption, and the

rate of intestinal hydrolysis of the acetate

form.’3’6 Water-miscible preparations of free a-tocopherol appear to be absorbed efficiently after

intramuscular administration, unlike the tocoph-erol acetate suspended in oil, which is absorbed less well.’6 The mean half-life for d,l-a-tocopherol in the very-low-birth-weight infant is reported as ap-proximately 44 hours after intramuscular’4 and 282

± 164 hours after intravenous administration.15

The reason(s) for the extreme variability reported for the half-life of a-tocopherol given by parenteral route is not known.

The adequacy of vitamin E status in a newborn infant has been difficult to determine. Vitamin E requirements are directly related to the polyunsat-urated fatty acid content in the diet, plasma, and tissues.’7 One method of assessing stability of lipid

membranes, and presumably the adequacy of

an-tioxidant protection, is the in vitro peroxide he-molysis test. Vitamin E has been shown to improve red cell membrane stability and decrease the tend-ency to hemolysis in preterm infants. Although most premature infants are deficient at birth,’8 plasma concentrations of a-tocopherol reach nor-mal adult levels of 0.5 to 2.5 mg/dL’9 (and hemol-ysis tests are normal) within several days after

feeding human milk or (vitamin E fortified) com-mercially available formulas.

Although tocopherol is thought to be relatively

nontoxic, excess ingestion or administration in

adult man and animals has been associated with

creatinuria,#{176} decreased platelet aggregation,2’ im-paired wound healing,22 the potentiation of vitamin K deficiency coagulopathy,23 anti-inflammatory ac-tivity,24 hepatomegaly with discoloration of the liver,25 impaired fibrinolysis,26 and irritation at the site of local injection.27 Toxicity in the preterm infant has also been seen as a symptom complex associated with respiratory distress, renal failure, liver disease, ascites, thrombocytopenia, and death. This syndrome has been related to the intravenous

administration of a specific vitamin E preparation

(E-Ferol Aqueous Solution, O’Neal, Jones and

Feldman, St. Louis) now withdrawn from the mar-ket.28 It has not been determined whether the tox-icity associated with E-Ferol administration is re-lated to excessive tocopherol levels, emulsifying agents used to solubilize the tocopherol, sudden changes in plasma osmolality, or other factors.

In individual very-low-birth-weight infants, we do not know the plasma level at which the risk of vitamin E toxicity changes significantly. An in-creased incidence ofbacterial sepsis and necrotizing enterocolitis was found in premature infants ex-posed to sustained serum vitamin E levels of ap-proximately 4.5 mg/dL,7 and Phelps has reported an increase in the frequency of intracranial

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COMMENTARIES

627

orrhage in infants weighing less than 1,000 g after the intravenous administration of free

a-tocoph-erol. However, there are many unanswered

ques-tions about the formulation, route of administra-tion, and plasma concentration as they may relate to vitamin E toxicity. In addition, we do not know

whether intermittent or sustained elevations of

plasma levels are more harmful; nor do we know

the relationship of plasma to tissue levels that ultimately may be the most important variable.

Vitamin E may prove to be of benefit to the very-low-birth-weight infant, although this conclusion

must await further data. Like many other

phar-macologic agents used in premature infants, how-ever, serial monitoring of plasma levels appears to

be a necessary guide to rational adjustments in

dosage. This seems particularly important if vi-tamin E is to be used widely, prophylactically, and for extended periods in this vulnerable population.

JAMES A. LEMONS, MD

Indiana University School of Medicine James Whitcomb Riley Hospital for Children Indianapolis

M. JEFFREY MAISELS, MB, BCh

The Milton S. Hershey Medical Center The Pennsylvania State University Hershey

REFERENCES

1. Owens WC, Owens EU: Retrolental fibroplasia in premature infants: II. Studies on the prophylaxis of the disease: The use of alpha tocopheryl acetate. Am J Ophthalmol 1949;32:1631

2. Johnson L, Schaffer D, Boggs TR Jr The premature infant, vitamin E deficiency and retrolental fibroplasia. Am J Clin Nutr 1974;27:1158-1170

3. Finer NN, Grant G, Schindler RF, et al: Effect of

intramus-cular vitamin E on frequency and severity of retrolental fibroplasia: A controlled trial. Lancet 1982;2:1087-1091 4. Hittner HM, Godio LB, Rudolph AJ, et al: Retrolental

fibroplasia: Efficacy of vitamin E in a double-blind clinical study ofpreterm infants. NEngIJ Med 1981;305:1365-1371 5. Speer ME, Blifeld C, Rudolph AJ, et al: Intraventricular

hemorrhage and vitamin E in the very low birth weight infants: Evidence for efficacy ofearly intramuscular vitamin E administration. Pediatrics 1984;74:1107-1112

6. Phelps DL: Vitamin E and retrolental fibroplasia in 1982. Pediatrics 1982;70:420-425

7. Johnson L, Bowen FW Jr, Abbasi S, et al: Relationship of prolonged pharmacologic serum levels of vitamin E to mci-dence of sepsis and necrotizing enterocolitis in infants with

birth weight 1,500 grams or less. Pediatrics 1985;75:619-638 8. Hittner, HM, Kretzer FL, Rudolph AJ: Prevention and

management of retrolental fibroplasia. Hospital Practice February 1984, pp 85-99

9. Hittner HM: Letter to the Editor. Pediatrics 1984;74:565-569

10. Ehrenkranz RA: Vitamin E and the neonate. Am JDiS Child 1980;134:1157-1166

11. Knight ME, Roberts RI: Disposition of pharmacological doses ofvitamin E in newborn rabbits, Abstract 349. Pediatr Res 1984;18:154A

12. Hansen LG, Warwick WJ: A fluorometric micro method for serum tocopherol. Am J Clin Pat/wI 1966;46:133-138

13. Colburn WA, Ehrenkranz HA: Pharmacokinetics of a single intramuscular injection of vitamin E to premature neonates. Pediatr Pharmacol 1983;3:7-14

14. Bhat R, Braun RJ: Pharmacokinetics of exogenous vitamin E in the newborn, Abstract 322. Pediatr Res 1984;18:149A 15. Myers PR, Quissell RI, Peterson RG: Pharmacology of

intravenous vitamin E in the very low birth weight (VLBW) newborn, Abstract 366. Pediatr Res 1984;18:157A

16. Pantoja A, Ukrainski C, Belenky D, et al: Vitamin E (VE) kinetics in infants <1500 grams: Intramuscular (IM) vs. oral administration, Abstract 371. Pediatr Res 1984;18:157A

17. Bell EE, Filer U: The role of vitamin E in the nutrition of premature infants. Am J Clin Nutr 1981;34:414-422

18. Gutcher GR, Raynor WJ, Farrell PM: An evaluation of vitamin E status in premature infants. Am J Clin Nutr 1984;40:1078-1089

19. Bieri JG, Corash L, Hubbard VS: Medical uses of vitamin E. N Engl J Med 1983;308:1063-1071

20. Hillman RW: Tocopherol excess in man: Creatinuria

asso-ciated with prolonged ingestion. Am J Clin Nutr

1957;5:597-600

21. Stuart MJ, Oski FA: Vitamin E and platelet function. Am J Pedietr Hematol Oncol 1979;1:77-82

22. Ehrlich HP, Tarver H, Hunt TK: Inhibitory effects of vitamin E on collagen synthesis and would repair. Ann Surg 1972;175:235-240

23. Corrigan JJ Jr, Marcus Fl: Coagulopathy associated with vitamin E ingestion. JAMA 1974;230:1300-1301

24. Levy L: The antiinflammatory action of some compounds with antioxidant properties. Inflammation 1976;1:333-345

25. Phelps DL: Toxicity of pharmacologic parenteral doses of vitamin E in the neonatal kitten. Pediatr Res 1979;13:372

26. Moroz LA, Gilmore NJ: Inhibition of plasmin-mediated fibrinolysis by vitamin E. Nature 1976;259:235-237

27. Smith IJ, Buchanan MFG, Goss I, et al: Vitamin E in retrolental fibroplasia, Letter to the Editor. N Engl J Med 1983;309:669-670

28. Lorch V, Murphy MD, Hoersten LR, et al: Unusual syn-drome among premature infants: Association with a new intravenous vitamin E product. Pediatrics 1985;75:598-602 29. Phelps, DL: Vitamin E and CNS hemorrhage. Pediatrics

1984;74:1113-1114

Prevention

of Pertussis-Are

We Failing?

Through the years, a system has evolved to assure that children are protected against pertussis and other infectious diseases. Its success is attested to by the dramatic decline in diseases caused by the organisms these vaccines are designed to prevent. The infrastructure upon which this system is

de-pendent has been invisible. Components become

apparent only as we become concerned about its

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How Much Is Too Much?

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How Much Is Too Much?

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Vitamin E

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