Vitamin E Toxicity

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REFERENCES

1. Hittner HM, Speer ME, Rudolph AJ, et al: Retrolental fibroplasia and vitamin E in the preterm infant-Compari-son of oral versus intramuscular:oral administration.

Pedi-atrics 1984;73:238-249

2. Johnson L, Bowen F, Herrmann N, et al: The relationship of prolonged elevation of serum vitamin E levels to neonatal bacterial sepsis and necrotizing enterocolitis. Pediatr Res 1983;17:319A

3. Guggenheim MA, Ringel SP, Silverman A, et al: Progressive neuromuscular disease in children with chronic cholestasis and vitamin E deficiency: Diagnosis and treatment with a-tocopherol. J Pediatr 1982;100:51-58

In

Reply.-Sokol incorrectly asserts that we have extended our observations regarding pharmacologic vitamin E therapy. In all of our clinical studies, which include 418 high-risk preterm infants,’3 the infants have consistently main-tamed mean plasma vitamin E levels below 3.5 mg/100 mL, which are within the adult physiologic range.

Sokol is concerned that our table 3 (reference 3, page 243) includes the clinical data (excluding Apgar scores) for only the 135 infants who survived 10 weeks. Data (including Apgar scores) for all 168 infants are presented in Table 1. These data demonstrate that the two popu-lations are totally comparable despite the fact that there were more deaths among the infants with birth weight 1,00O-g in the control group (16 v six infants).

Sokol questions the recommendation that early intra-muscular (IM) vitamin E therapy should be given “on the first day of life to decrease infant mortality” because our table 4 (reference 3, page 243) does not list the sepsis, necrotizing enterocolitis, and intraventricular hemor-rhage data for the entire 168-infant population. The significance of decreased infant mortality for all 71 in-fants of 1,000-g birth weight enrolled on the randomized double-masked clinical trial was P .03. Despite this

statistical significance, these data for all 168 infants are presented in Table 2, and values are commensurate with the data published in reference 3 and in the parallel abstract on intraventricular hemorrhage.4 Because the control group was comparable to the treatment group without excluding early infant deaths, it is justifiable to conclude that early IM injections do decrease mortality without inducing toxicity when the mean plasma vitamin

E levels never exceed the adult physiologic maxima of 3.5 mg/100 mL.

Sokol misunderstands the four vitamin E-induced tox-icities which have been reported in high-risk preterm infants: ( 1 ) Hyperosmolar oral preparations can induce necrotizing enterocolitis.’ (2) Obtaining mean peak vi-tamin E levels 8 mg/100 mL by IM and/or intravenous

(IV)

administration6

can

induce

sepsis

and

necrotizing

enterocolitis.7 (3) Repeated oil-based IM injections8 cause local tissue necrosis and calcification.9 (4) Daily IV ad-ministration of 25 mg/kg of tocopheryl acetate in poly-sorbate 80 in parenteral alimentation solutions is asso-ciated with a syndrome consisting of ascites, hepatosple-nomegaly, cholestatic jaundice, azotemia, thrombocyto-penia, and death.’#{176}Our reported randomized double-masked clinical trial did not utilize a hyperosmolar oral preparation, administer an oil-based IM product, exceed the 3.5 mg/100 mL plasma vitamin E maxima suggested by the Food and Drug Administration or suggest IV

administration.

Sokol is correct that necrotizing enterocolitis is a spo-radic entity and that historic controls cannot be used for statistical comparison. However, the incidence of necro-tizing enterocolitis induced by hyperosmolar oral admin-istration and plasma vitamin E levels 8 mg/100 mL produced by IM and IV administration is of a completely different magnitude. The Texas Children’s Hospital Neo-natal Intensive Care Unit had a 4% to 6% incidence of

TABLE 1. Clinical Factors in Control (Oral Vitamin E) and Treatment (IM:Oral Vitamin

E) Groups in 1982 Randomized Double- Masked Study

Control Infants Treatment Infants

Enrolled 1,500 g [n

=

89] [n = 79]

No. % No. %

Gestational age (wk)

27 31 34.8 23 29.1

28-29 27 30.3 30 38.0

30-31 22 24.7 21 26.6

32 9 10.1 5 6.3

Mean ± SD 28.4 ± 2.4 28.5 ± 2.1

Birth weight (g)

750 15 16.9 8 10.1

751-1,000 23 25.8 25 31.6

1,001-1,250 29 32.6 23 29.1

1,251-1,500 22 24.7 23 29.1

Mean ± SD 1,055 ± 253 1,077 ± 246

Outside births 19 21.3 15 19.0

Apgar score

1 mm (±SD) 4.7 ± 2.5 5.0 ± 2.2

5 mm (±SD) 7.3 ± 1.7 7.4 ± 1.7

Pneumothorax 9 10.1 5 6.3

Bronchopulmonary dysplasia 17 19.1 17 21.5

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TABLE

2. Controversial

Clinical

Factors

in Control

(Oral

Vitamin

E) and

Treatment

(IM:Oral Vitamin E Groups in 1982 Randomized Double-Masked Study

Control Infants Treatment Infants

Enrolled 1,500 g En= 89] [n = 79]

1,000g [n=38] [n=33]

No. % No. %

Mortality

1,500g 23 25.8 14 17.7

1,0o0

g 16 42.1 8 24.2

Sepsis

1,500 g 14 15.7 11 13.9

1,0oo

g 6 15.8 7 21.2

Necrotizing enterocolitis

1,500g 4 4.5 4 5.1

<1,000g 3 7.9 1 3.0

Intraventricular

hemorrhage

sl,500 g: Grade

I

13

14.6

13

16.5

Grade

II

11

12.4

4

5.1 Grade

III

4 4.5 4 5.1

Grade

IV

3

3.4

1 1.3

Total 31 34.8 22 27.8

1,000g:GradeI

6 15.8 5 15.2

Gradell

6

15.8

4 12.1

Gradelil

3

7.9

2 6.1

Grade

IV

2 5.3 1 3.0

Total

17 44.7 12 36.4

necrotizing

enterocolitis

from

1980 to 1982. This is

dis-tinct

from

the

13.4%

induced

by hyperosmolar

loading

(v

5.7% without an osmolar load)5 and the 30% caused by

plasma

vitamin

E levels

8 mg/100

mL

(v 4%

with

plasma

vitamin

E levels

3.5 mg/100

mL).6

Our

recommendation

to

administer

three

early

IM

injections

“of the

best

available

preparation

of vitamin

E” was made

in August

1983. This recommendation was

based on the established pharmacokinetics of aqueous

parenteral

vitamin

E administration”

(Fig

1).

Clearly,

IM injections

of the alcohol

are superior

to those

of the

slowly

hydrolyzed

acetate.

However,

subsequent

to IM or

IV injections,

measurable

plasma

tocopherol

levels

are

obtained

for both

alcohol

and acetate

preparations.

Our

clinical trial3 demonstrated a rapid elevation of plasma

vitamin

E levels

by

aqueous

tocopherol,

Ephynal

IM,

used

in combination

with

oral

tocopheryl

acetate

(100

mg/kg/d) in MCT (medium-chain triglycerides) oil as

compared

with

only

oral

administration

(Fig

2, A).3 It

was

hoped

that

the

preterm

infants’

deficient

plasma

levels could be quickly elevated to adult physiologic

plasma

vitamin

E levels

utilizing

the

only

commercially

available

IM vitamin

E preparation.

However,

in April

1984, data

became

available

that

demonstrated

poor

ab-sorption

and

hydrolysis

of the oil-based

tocopheryl

ace-tate,

E-ferol

IM, used in combination

with oral tocopheryl

acetate (100 mg/kg/d) in Tween 80 with propylene glycol as compared with only the oral administration (Fig 2,

B).”

Additionally, in April 1984, Bhat and Braun’3”4 pub-lished abstracts that predict lack of efficacy in suppress-ing the development of severe retinopathy of prematurity for IV as compared with IM vitamin E administration

due to significantly

delayed

and decreased

retinal

uptake

following IV administration (Fig 3). A fast increase in retinal levels of tocopherol is critical because the etiology of retinopathy of prematurity is initiated by early bio-chemical events that are seen ultrastructurally as gap junction increases between adjacent spindle cells as early as 4 days of life.’5 This altered ionic coupling changes spindle cells from endothelial precursors to sites of syn-thesis and secretion of angiogenic factors. Vitamin E suppression of gap junction formation is dependent upon uptake of the antioxidant into retinal membranes.

The dose-response curves for oral (Fig 4, A),’6 IM (Fig

4,

B),’7

and IV (Fig 4, C)’8 vitamin E administration to

preterm high-risk infants are distinctly different. Oral vitamin E can be administered either as the alcohol or acetate preparation (Fig 4, A), but good absorption of IM and IV vitamin E is dependent on aqueous alcohol prep-arations (Fig 4, B and C). The vehicle has significance because of induced toxicities [oral (hyperosmolar related necrotizing enterocolitis) and IM (local tissue necrosis and calcification)] and maximized absorption [oral (MCT oil) and IM (aqueous base)].

Therefore, the preparations commercially available were suboptimal when administered to the high-risk pre-term infant for the following reasons: oral Aquasol E is hyperosmolar; E-ferol IM is an oil-based acetate (has been recalled); and E-ferol IV is an acetate in polysorbate 80 (has been recalled). The pediatric community should request their hospital pharmacists to prepare oral vitamin E in MCT oil’9 as recommended in our article’ and await

FDA

approval

of an IM aqueous

alcohol

vitamin

E. On

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prematur-10

8 7 E 0 E 0 0 0 I-E ‘I, (0

Single

Dose:

5mg/kg

(aqueous)

6

5

4

3

2

1

0

::::

-- .0

16

24

9

REFERENCES

HELEN M. HITFNER, MD

Department of Pediatrics and Cullen Eye Institute Baylor College of Medicine Houston, TX 77030

8 Time

(hours)

AIcohoI

IV. jAcetate

Fig 1. Pharmacokinetics of aqueous parenteral vitamin E administration. Resultant plasma tocopherol levels are shown for the first 24-hour period following single 5 mg/ kg-dose to dogs of: intramuscular (IM) tocopherol (open circles with solid line); (IV) tocopherol (solid circles with solid line); IM tocopheryl acetate (open circles with dashed line); and IV tocopheryl acetate (solid circles with dashed line). Data from Newmark et al.’1

ity) regarding vitamin E administration (emphasizing the first week of life). It is hoped that this preparation (aqueous alcohol) will soon be approved for IM use in the high-risk preterm infant to suppress the development of severe retinopathy of prematurity,’3’20” to decrease mortality,3 and to decrease the incidence and severity of intraventricular hemorrhage.4’23 Further, the term par-enteral to include IM and IV preparations should be avoided, as IV administration, although safe for the high-risk preterm infant in adult physiologic doses,24 is un-warranted and nonefficacious in preventing the develop-ment of severe retinopathy of prematurity.

1. Hittner HM, Godio LB, Ruldoph AJ, et al: Retrolental fibroplasia: Efficacy of vitamin E in a double-blind clinical study of preterm infants. N Erigi J Med 1981;305:1365 2. Hittner HM, Godio LB, Speer ME, et al: Retrolental

fibro-plasia: Further clinical evidence and ultrastructural support for efficacy of vitamin E in the preterm infant. Pediatrics

1983;71:423

3. Hittner HM, Speer ME, Rudolph AJ, et al: Retrolental fibroplasia and vitamin E in the preterm infant-Compari-son of oral versus intramuscular:oral administration.

Pedi-atrics 1984;73:238

4. Speer ME, Blifeld C, Rudolph AJ, et al: Intraventricular hemorrhage (IVH) & vitamin E (VE) in very low birth weight infants: Efficacy of early IM administration. Pediatr

Res 1984;18:383A

5. Finer NN, Peters KL, Hayek Z, et al: Vitamin E and necrotizing enterocolitis. Pediatrics 1984;73:387

6. Sobel 5, Gueriguian J, Troendle G, et al: Vitamin E in retrolental fibroplasia, letter. N Engi J Med 1982;306:867 7. Johnson L, Bowen F, Herrmann N, et al: The relationship

of prolonged elevation of serum vitamin E levels to neonatal bacterial sepsis (SEP) & necrotizing enterocolitis (NEC).

Pediatr Res 1983;17:319A

8. Hittner HM, Kretzer FL, Rudolph AJ, et al: Vitamin E in retrolental fibroplasia, letter. N Engi J Med 1983;309:669 9. Smith IJ, Buchanan MFG, Goss I, et al: Vitamin E in

retrolental fibroplasia, letter. N Engi J Med 1983;309:669 10. Lorch V, Murphy MD, Hutcheson RH, et al: Unusual

syn-drome with fatalities among premature infants: Association with a new intravenous vitamin E product. MMWR 1984;33:198

11. Newmark HL, Pool W, Bauernfeind JC, et al: Biopharma-ceutic factors in parenteral administration of vitamin E. J

Pharm Sci 1975;64:655

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

13. Bhat R, Braun RJ: Pharmacokinetics of exogenous vitamin E in the newborn. Pediatr Res 1984;18:149A

14. Bhat R, Braun RI: Retinal and tissue vitamin E kinetics in the newborn kitten following vitamin E administration.

Pediatr Res 1984;18:149A

15. Kretzer FL, Mehta RS, Johnson AT, et al: Vitamin E protects against retinopathy of prematurity through action on spindle cells. Nature 1984;309:793

16. Bell EF, Brown EJ, Milner R, et al: Vitamin E absorption in small premature infants. Pediatrics 1979;63:830

17. Colburn WA, Ehrenkranz RA: Pharmacokinetics of a single intramuscular injection of vitamin E to premature neonates.

Pediatr Pharm 1983;3:7

18. Myers PR, Quissell BJ, Peterson RG: Pharmacology of intravenous vitamin E in the very low birthweight (VLBW) newborn. Pediatr Res 1984;18:157A

19. Williams ML, Oski FA: Vitamin E status of infants fed formula containing medium-chain triglycerides. J Pediatr 1980;96:70

20. Johnson L, Schaffer D, Boggs TR: The premature infant: Vitamin E deficiency and retrolental fibroplasia. Am J Clin

Nutr 1974;27:1158

21. 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;1:1087

22. Finer NN, Schindler RF, Peters KL, et al: Vitamin E and retrolental fibroplasia: Improved visual outcome with early vitamin E. Ophthalmology 1983;90:428

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E

8

E

0

-C

0

E

(0

a-4

3

2

1

0

r4P

L .1. I I j___

0 1 2 3 4 6

t t t t

15ASAP 10 10 10

5

-J

1

I I I I I I I i

0 1 2 3 4 5 6 7

I t t f f $

5OASAP 20 20 20 20 20 20

80r-lime (days)

Fig 2.

Comparison

of plasma

tocopherol

levels

for two protocols

of intramuscular

(IM):

oral

v

oral

vitamin

E administration

in high-risk

preterm

infants.

Plasma

tocopherol

levels

are

shown

for the

first 7 days of life. Hatched area represents adult physiologic

range

for vitamin

E. A, IM Ephynal

+

oral

TCH

(Texas

Children’s

Hospital)-E

produces

significantly

higher

plasma

tocopherol

levels

than

oral TCH-E

alone.

First

dose of

15 mg/

kg of Ephynal should be given as soon as possible following delivery. B, IM E-ferol + oral

Aquasol

E does

not produce

higher

plasma

tocopherol

levels

than

oral

Aquasol

E alone.

The

IM E-ferol

injections

are much

higher

on a milligram

per kilogram

basis

than

the IM

Ephynal

injections;

however,

oil-based

acetate

is less well utilized

than

aqueous

alcohol.

Data

from

Hittner

et al3 (A) and

Pantoja

et al”

(B).

- * Ephynal#{174} 100mg/kg I .V. ---- = Ephynal#{174}100mg/kg I .M.

(aqueous alcohol) (aqueous alcohol)

Biochemical events

r

initiating ROP

300 ‘ Ultrastructural

alterations

documented in ROP

200

100

A

E

8

E

0

w

-C

0

(0

E

(0

a-60

40

20

0

B

C

.

E

0

-C 0.

0

I-(0

C

4)

lime (days)

0 1 2 3 4 5 0’

I I I

3 4 5

A

- - Ephynal#{174}(-0. . mq/kq I .M. alcohol

in water) and ICH-E

---- . ICH-E (lOOmq/kq oral acetate in

MCI oil)

B

- . E_ferol#{174}(___.. . mg/kg I .M. acetate

..

#{174}

in oil) and Aquasol E

---- . Aquasol E#{174}(100mg/kg oral acetate in

Iween 80 with Propylene glycol)

Fig 3.

Comparison of plasma v retinal tocopherol levels in kitten following intravenous

(IV)

and

intramuscular

(IM)

administration

of 100 mg/kg

of Ephynal

shown

for first

5

days of life. A, Plasma tocopherol levels are shown to be adequate following IV or IM

administration;

however,

kinetics

for

IV is less

ideal

than

for

IM

administration.

B,

Retinal

tocopherol

levels

are

twice

as high

in one

third

the

time

for

IM

than

for IV

administration.

Thus,

because

of plasma

pharmacokinetics

and

resultant

retinal

levels,

IM administration

of vitamin

E is preferred

for altering

biochemical

events

initiating

(5)

Less

than 40% absorption with biliary

and pancreatic

secretions

present.

E

0

4)

-C

0

U

0

(0 E

(I’

(0

a-

8-

6-

4-

2’-0

(T

0

24

48

0

24

48

0

I I I I

48

24

10

-A

Single

P.O. Dose

25mg/kg

(alcohol

or acetate)

B

Single I.M.Dose

Ephynal#{174}2Omg/kg

(aqueous alcohol)

C

Single I.V.Dose

Ephynal#{174}

10mg/kg

(aqueous alcohol)

Time (hours)

Fig 4. Comparison of plasma tocopherol levels achieved by oral, intramuscular (IM) and intravenous (IV) administration of tocopherol in high-risk preterm infants for first 48 hours following single dose. A, Oral administration of 25 mg/kg of either alcohol or acetate of vitamin E does not raise plasma tocopherol level to adult physiologic range (hatched area) because of poor absorption in preterm small intestine. B, IM administration of 20 mg/kg of Ephynal produces plasma tocopherol levels peaking at 6 mg/100 ml and falling slowly (half-life of 44 hours). C, IV administration of 10 mg/kg of Ephynal yields plasma tocopherol levels that approach 9 mg/100 mL and then rapidly decline. These pharmaco-kinetics can be utilized to plan IM:oral protocols for the preterm infant. IV administration is not recommended. Data from Bell et al’6 (A), Colburn et al’7 (B), and Myers et al’8 (C).

effect of vitamin E (DL-alpha-tocopherol) against intraven-tricular hemorrhage in premature babies. Br Med J

1983;287:81

24. Phelps DL, Rosenbaum A, Leake RD, et al: Safety of intra-vascular tocopherol in a randomized double blind trial in premature infants. Pediatr Res 1984;18:158A

A Pediatrician’s

Program

for the Prevention

of Dental

Caries

in the First Years

of Life

To the

Editor.-Inasmuch as infants and children usually do not visit a pedodontist or a dentist in the first few years of life, I have recently undertaken a dental prophylactic program.

The program consists ofthree approaches: (1) Fluoride supplementation is started in the first 2 weeks of life whenever the infant is ready to use formulas, or when well water with inadequate fluoride content is used. This consists of 0.25 mg of fluoride with the usual vitamin drops and later vitamin tablets with fluoride until the infant is seen by the family dentist. (2) As soon as the

first incisor tooth erupts adequately, the mothers are instructed to brush after dinner and later after breakfast either with no toothpaste or with a touch of fluoride-containing gel toothpaste. No bottle is permitted once the teeth have been brushed. Parental help is necessary for the younger children. (3) An educational program toward reducing sugar intake is instituted with the aid of instructional sheets. The parents are told to show this information to the grandparents also.

Using this program, the first 100 children were ana-lyzed after their first dental visit. The result was that 94% of them were caries-free at 3 to 4 years of age. A second gratifying finding was that with early establish-ment of the brushing habit, 92% of the children liked or loved to brush their teeth.

All six of the children with caries gave a history of moderately heavy sugar intake.

I urge

other

pediatricians

to use such

a program

and

to distribute the pamphlets “Your Child’s Teeth” and “The Care of Children’s Teeth” (obtainable from the American Dental Association, 211 E Chicago Aye, Chi-cago, IL 60611) in their practices. Copies of my instruc-tion sheets are available on written request to me.

SUMNER HAGLER, MD

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1984;74;565

Pediatrics

HELEN M. HITTNER

Vitamin E Toxicity

Services

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http://pediatrics.aappublications.org/content/74/4/565

including high resolution figures, can be found at:

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