Hexachlorophene Storage in a Burn Patient Associated With Encephalopathy

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ABSTRACT. Hexachlorophene (HCP), a chlorinated phe nolic hydrocarbon with bacteriostatic properties against Staphylococcus, is used in a number of topical products. Al)sorptioll through normal and damaged human skin has l)eefl appreciated and neurologic changes have been

described in experiniental aninials, but instances of human toxicity have been reported infrequently. A 10-year-old boy who sustained a 25% burn did well initially but died in the

second week of convalescence with hvpertherniia, lower extremity weakness, and cerel)ral edema. His treatment had

included frequent applications of HCP. Analysis of post mortem tissue revealed the presence of toxic levels of HCP in the blood (2.2jsg/gm) and brain (2.2jsg/gm), with storage in

skin (25@sg/gm). liver (4.4@sg/gm), and fat (6.Ojig/gm). This

case suggests that topical applications of HCP in man may result in an extensive absorption with fat storage and may cause fatal encephalopathv. Pediatrics, 59:457-459, 1977,

HEXACHLOROPHENE, BURNS, ENCEPHALOPATHY.

baths have approached levels seen in symptomat

ic rats prompted restrictions in its usage. It has been suggested, however, that HCP may be less

toxic for humans than animals at similar blood levels'; indeed, there have been remarkably few well-studied cases of HCP poisoning reported.

\Ve investigated HCP blood and tissue levels in a

10-year-old boy who sustained an uncomplicated moderate burn and who was treated with exten sive topical applications of diluted and undiluted

3%HCP.He died after progressiveweaknessand

coma despite satisfactory wound healing. These studies shed additional light on the clinical toxi colog@ of HCP and its distribution after absorp

tion in man.

CASE REPORT

A 10-year-old svhite boy was transferred to Strong Memo

rial Hospital. Two weeks earlier, a small gasoline engine had exploded OIl ignition, resulting in a 25% partial thickness

(Received March 8; revision accepted for ptillicatioli May 5,

1976.)

ADDRESS FOR REPRINTS: (R.R.C.) Department of Pecli

atrics, Michael Reese Hospital, 29(X) South Ellis Avenue, Chicago, Illinois 60616.

Hexachlorophene (2,2'-methylenebis(3,4,6,-tri chlorophenol); HCP) has been used in a variety of topical products and, in the past, was used in the treatment of burn patients because of its bacteri ostatic properties against coagulase-positive Sta pliylococcus. Recent reviews have underscored HCP's potential toxicity,@' and the fact that HCP

blood levels in newborns receiving daily 3% HCP

PEDIATRICS Vol. 59 No. 3 March 1977 457

HexachloropheneStorage in a Burn Patient

Associated With Encephalopathy

Robert Chilcote, M.D., August Curley, M.A., Howard H. Loughlin, M.D., and John A.

Jupin, M.D.

I'ron, the Dcpartnzents ofPediatrics and Pathology, Unicersitt, ofRocl,ester SeI@oolof â€˜¿sf('(liei?ie(111(1Dentistrij,

Rochester, New York, and t!ze Enciron,nental Protection Agency, Cliamblee Toxicology Laboratory. C1,a@nblee, Georgia

at Viet Nam:AAP Sponsored on September 8, 2020 www.aappublications.org/news

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TissueHCP (pg/gm)Blood12 hr after discontinuation2.236 hr after discontinuation2.1Postmortem2.9Brain2.2Skin (unburned abdominal wall)25.0Liver4.4Muscle2.4Kidney2.2Fat

(subcutaneous abdominal wall)6.0 TABLE I

TISSUE LEVELS OF HEXACHLOROPHENE

silica-gel microcolumns. The eluate was analyzed by electron capture gas-liquid chromatography. Results are expressed as micrograms of HCP per gram of tissue.

RESULTS

All tissues studied contained high levels of HCP (Table I). The whole blood level of 2.2jig/gm on

admission was unchanged at the time of death.

Samples of brain, kidney, and muscle yielded

HCP levels similarto blood levels. Liver and fat

levels exceeded the blood level. A specimen of the

patient's unburned abdominal wall skin was par ticularly high in HCP content, measuring 25jig/ gm.

DISCUSSION

HCP is a halogenated bisphenol introduced to replace phenol when systemic toxicity precludes direct skin application. Gump, however, noted in

his review of HCP toxicity that single applica

tions of 15% HCP were lethal to experimental animals, while daily applications of 3% HCP

caused â€œ¿toxicityâ€•in experiments carried out in

1951.6 Herter7 noted a newborn who received 3%

HCP applicationsand developed a full fontanel

and seizures. Larson@ reported eight patients who developed seizures, diplopia, lower-extremity weakness, nausea, vomiting, and irritability in the course of topical HCP applications for burns. These symptoms cleared when HCP administra tion was stopped; there were no deaths. Larson

also noted that control animals, as well as burned

animals, died after repeated exposures to topical

3% HCP. Kimbrough and Gaines' have reviewed

the animal literature and note that symptoms of toxicity include hind-quarter weakness, cystic

spaces or vacuolization of the white matter, and

cerebral edema. The absence of cystic spaces in the white matter of this patient at autopsy suggests that HCP leaves no specific lesion after two weeks of exposure in man.

Uncoupling of rnitochondrial oxidative phos

phorylation occurs at concentrations of HCP as

low as ljig/mg.'â€• This patient had tissue levels

from 2- to 25-fold higher, indicating that his blood

and tissue concentrations were sufficient to cause

toxicity and hyperthermia. Electrolyte dilution is associated with a variety of cerebral insults,

though definitive data to document inappropriate antidiuretic hormone in this patient are lacking.

Little is known of the uptake and distribution of HCP. Absorption through normal skinm2m1 and burn to his right side without pulmonary involvement.

Treatment was begun with oral fluids and, during the first two hospital days, his burns were covered with dressings soaked in a diluted 3% HCP cleansing solution (pHisoHex). Thereafter, his burns were left uncovered, and he had tub soaks prepared by adding 1 to 2 oz of this cleansing solution to a tub of water three to five times daily. The cleansing solution was diluted and sprayed directly to the healing burn

areas for the relief of itching. On the ninth day after his burn,

he complained, â€œ¿Idon't feel good all over,â€• and became increasingly uncooperative. His temperature rose to 38.9 C, but cultures were negative. Lower-extremity weakness developed and the patient appeared to be confused when he asked to â€œ¿helphang out the wash. â€œ¿There were no seizures. Blood pressure and respiration rate remained normal. On the 13th day after burn, he appeared to have difficulty breathing and he became apneic. After resuscitation, he was unrespon sive, with a blood pressure of 120/70 mm Hg and pulse rate of 120 beats per minute. Papilledema and bilateral rhonchi were noted. Urine specific gravity was 1.024. Sodium level was 124 mEq; potassium, 3.0 mnEq; chloride, 80 inEq; and blood urea nitrogen, 15 mg/liter. He was transferred to Strong Memorial Hospital but had no spontaneous respira tions, deep tendon reflexes, or response to pain; his pupils were fixed at midpoint. Additional laboratory studies revealed a hematocrit reading of 34% and white blood cell count of 11,300/cu mm with 81% neutrophils. Arterial pH was 7.45. Blood culture yielded no growth. The patient required assisted ventilation amiddied the next day, approxi

mately 36 hours after the last HCP treatment.

Autopsy revealed satisfactorily healing burns, pneumonia compatible with aspiration, and cerebral edema (brain weight 1,390 gum) with swollen gyri and compressed sulci.

Sections showed nonspecific edema of both gray amid white

matter without cystic spaces, gliosis, inclusion bodies, or leukocyte infiltrate. Postmortem cultures of blood, lung, brain, and spinal fluid were negative.

HEXACHLOROPHENESTUDIES

Studies were carried out at the Laboratory of the Environmental Protection Agency.5 Samples were extracted with ethanol ether, acidified and methylated with diazomethane, and purified on

458 HEXACHLOROPHENE

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cutaneous storage'5 have been previously docu

mmented. Burns increase HCP absorption by a

factor of 2Â½ in experimental animals, but in 24 hours absorption falls to preburn levels. â€˜¿â€œThis suggests that excessive skin exposure, rather than

altered permiieability, played the principal role in

toxicity. HCP is albumin-bound,'@ with an esti

miiated blood half-life of ten hours amidexcretion in

the stool and urine.'5 Frequent

exposure likely

resulted in a net tissue accumulation.

Tissue levels in this patient would suggest a three-comnpartmnent mmodel: absorption and stor age in the skin, distribution by the blood, and deposition of unexcreted amounts in fat. Blood levels in exposed patients would vary in a complex fashion depending on paramneters such as degree of fat storage, liver function, and excre tion. Dialysis or exchange transfusion, as suggested in pentachlorophenol poisoning' where tissue storage is not appreciable, would not l)e effective. More importantly, isolated blood levels may not accurately reflect tissume levels where HCP is active. Further studies are imidi cated to determiiine the therapeutic index of HCP

and to clarify the relationships between absorp

tion, excretion, fat storage, and neurotoxicity.

REFERENCES

1. Kimbrough RD: Review of recent evidence of toxic effects of hexachlorophene. Pediatrics 51:391,

1973.

2. Lockhart JD: How toxic is hexachlorophene? Pediatrics

50:229, 1972.

:3. Kimbrotigh RD: Review of the toxicity of hexachloro

phene. Arch Environ Health 23: 1 19, 1971.

4. American Academy of Pediatrics Committee on Fetus and Newborn: Hexachlorophene and skin care of

newborn infants. Pediatrics 49:625, 1972,

5. Curley A, Hawk RE: Hexachlorophene: I. Analysis in body fluids and tissues of experimental animals. Presented at the 161st meeting of the American Chemical Society, Los Angeles, California, March 28-April 2, 1971.

6. Gump WS: Toxicological properties of hexachloro phene. J Soc Cosmetic Chemists 20:173, 1969. 7. Herter WB: Hexachlorophene poisoning. Kaiser Fotin

dation Med Bull 7:228, 1959.

8. Larson DL: Studies show hexachlorophene causes burn

syndrome. Hospital Assoc 42:63, 1968.

9. Kinibrough RD. Gaines TB: Hexachlorophene effects on the rat brain: Study of high doses by light and electron microscopy. Arch Environ Health 2:3:114, 1971.

10. Nakaue HA, Caldwell RS, Buhler DR: Bisphenolsâ€”un

couplers of phosphorylating respiration. Biochemii

Pharmacol 21:2273, 1972.

11. Camnier \V, Moore CL: The effect of hexachlorophene on the respiration of brain and liver mitochondria.

Biochem Bioph@s Res Commun 46: 1887, 1972.

12. Feldmann RJ, Maibach HI: Absorption of sonic organic

compounds through the skin in man. J Invest Dermatol 54:399, 1970.

13. Curle@ AV, I-Iawk RI, Kimbrough RD. et al: 1)ermal absorption of hexachlorophene imi infamits. Lancet

2:296,1971.

14. Kopelnian AE: Cutaneous al)sorption of hexachloro phene in low-birth-weight infamits. J Pediatr 82:972,

1973.

15. Shemano I, Nickerson NI: Cutaneous accumulation and

retention of hexachlorophene-C,4 (G-1 1). Fed Proc

13:404, 1954.

16. Carroll FE, Salak WW, Howard JM, et al: Absorption of

antimicrobial agents across experimental wounds. Surg Cynecol Obstet 125:974, 1967.

17. (;amidolfi AJ, Dost FN, Buhler DR: Absorption, excretion and nietabolism of hexachlorophene in the rat and rabbit. Fed Proc 31:6O5Abs, 1972.

18. \Vit JG, Van Gendersen H: Some aspects of the fate of hexachlorophene. Acta Physiol Pharniacol Neerlan dica 11:123, 1962.

19. Robson AM, Kissane JM, Elvick NH, et al: Pentachloro

phenol poisoning in a nursery for newborn infants:

I. Clinical features and treatment. J Pediatr 75:309, 1969.

ARTICLES 459

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1977;59;457

Pediatrics

Robert Chilcote, August Curley, Howard H. Loughlin and John A. Jupin

Hexachlorophene Storage in a Burn Patient Associated With Encephalopathy

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1977;59;457

Pediatrics

Robert Chilcote, August Curley, Howard H. Loughlin and John A. Jupin

Hexachlorophene Storage in a Burn Patient Associated With Encephalopathy

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