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EVALUATION OF THE SYSTEMIC TOXICITY OF PHENOL ON FACIAL PEELINGS

Bogdana Victoria Kadunc1, Adriana Amorim Vanti1

Received on 19/02/2009.
Approved on 25/02/2009.
We declare no conflict of interest.

Abstract

Introduction: Phenol has been used in medicine for several decades, but many aspects of its systemic toxicity are not completely known.
Objective: Evaluating the renal and cardiac toxicities of phenol absorbed percutaneously in facial peelings.
Material and methods: A prospective, comparative, randomized study was undertaken with 4 groups of 15 patients each, with 4 different types of facial peelings: pure, at 50 and 88% in continuous applications, pure at 88%, and associated with Baker’s Formula with applications at specific time intervals. Urinary levels of this substance were determined by gas chromatography and cardiac changes by a continuous electrocardiogram for 24 hours (Holter).
Results: Gas chromatography showed fast phenol elimination in the urine, with a half-life of 6 to 8 hours. Cardiac changes seen on the Holter were observed in all groups, which stopped immediately without medical intervention.
Conclusions: Phenol, used in facial peelings, does not affect renal function, but it can cause arrhythmias in susceptible individuals, which are not related with the concentration or technique used.

INTRODUCTION

Carbolic acid, or phenol, is an aromatic organic compound, derived from benzene, that has been used in medicine for several decades.1

Topically, it has immediate caustic action with the ability to promote denaturation and coagulation of epidermal keratin proteins, which translates into an immediate intense and uniform blanching of the skin.

It has several therapeutical indications in dermatology, including medium-depth and deep facial peelings used in the treatment of photoaging or acne scars.2

Deep chemical peelings with phenol, when properly indicated and conducted, produce results that cannot be compared to any other exfoliative method, may it be chemical, mechanical, or laser. However, it is knowingly a highly toxic drug.

Death has been reported after the oral ingestion of 5 to 40 g of phenol.3

It is rapidly absorbed when applied on the skin (70% of the volume used in 30 minutes).4 After absorption, 25% of this volume is metabolized to CO2 and water, and the remaining 75% follow one of the detoxifying pathways in the liver before being excreted by the kidneys: conjugation with sulfuric or glucuronic acid or oxidation. Some of it is excreted unchanged.5

Phenol can cause direct myocardial toxicity, leading to cardiac arrhythmias, and on blood vessels, causing hypotension.6

In 1985, Warner reported the case of a 10-year old patient who underwent treatment, under general anesthesia, of a giant melanocytic nevus, measuring 12 x 17 cm, with a topical solution containing 40% phenol and 0.8% croton oil. He presented premature multifocal ventricular contractions (PVCs), which were reverted with 50 mg of lidocaine IV.7

Therefore, special care is recommended when this drug is used: cardiac monitoring, intravenous infusion of high volumes to force diuresis, and slow and spaced applications to avoid kidney and cardiac lesions.

In literature reports, concentrations of phenol used in peelings vary from 30% and 90%,2 usually associated with different substances: croton or olive oil, cresol, sodium salicylate, camphor, glycerin, soaps, and ethanol, among others. The total volume of phenol, application methods, and types of dressings are not standardized, and Baker’s and Litton’s formulas, in which the final concentration of phenol is 50%, are mentioned more often.

Since, currently, this substance is widely used in facial rejuvenescence, most times as a component of patented formulas in which its final concentration is unknown, we concluded that there is a gap in the literature on the knowledge of its toxicity as an isolated agent.

Therefore, the objective of this study was to evaluate the renal and cardiac toxicity of phenol absorbed percutaneously, using urinary gas chromatography (UGC) and continuous 24-hour electrocardiogram (Holter) in patients receiving 4 different modalities of facial peelings: pure, at 50 and 88% in continuous applications, and pure, at 88%, and associated with croton oil, liquid soap, and distilled water, composing the Baker’s formula, in applications at different times.

MATERIAL AND METHODS

This was a prospective, comparative, randomized study with patients who were seeking facial aging treatment at the Dermatology outpatient clinic of the Hospital do Servidor Público de São Paulo.

This study received prior approval by the Ethics on Research Committee and it was developed according to good clinical practices. All patients signed an informed consent before the evaluation.

Sixty consecutive patients, phototypes II-III, according to Fitzpatrick’s classification, and with photoaging degrees III-IV, according to the Glogau classification, participated in this study. They received 4 different phenol peelings in the entire face and their renal and cardiac function were evaluated prior, during, and after the treatment.

Patients with a history of cardiac, including arrhythmias, renal and liver changes, diabetes, pregnant women, and women who were not using any safe contraceptive methods, nursing mothers, or women who had a tendency for depression were excluded. Patients who had undergone any facial aesthetic procedure the year before were also excluded. Among the patients included in the study, 18 had controlled mild to moderate hypertension.

The 60 volunteers were randomly divided into 4 groups, receiving a close, opaque envelope that indicated the instructions of their procedure,
- G1: continuous application of 50% phenol in alcohol;
- G2: continuous application of 88% phenol in alcohol;
- G3: 88% phenol in alcohol applied at 15-minute intervals among the 6 aesthetic units of the face (forehead, right malar, left malar, perioral, nose, and periocular);
- G4: Baker’s formula (3 ml of 88% phenol, 2 ml of distilled water, 3 drops of croton oil, and 8 drops of liquid soap) with a 15-minute interval among the 6 units and occlusion for 48 hours.,

After selection, they underwent clinical evaluation and laboratorial exams (CBC, glucose, BUN, creatinine, AST, ALT, GGTP, alkaline phosphatase, urinary density, and electrocardiogram), which were analyzed by an internist and a cardiologist.

Photographic records, standardized for distance and illumination, included frontal pictures and at 45° and 90° angles for the left and right hemiface.

Herpes simplex prophylaxis was instituted 2 days before peelings in all patients with 2,400 mg of oral acyclovir and continued for 10 days.

The procedure was performed at the outpatient clinic, in a room with adequate ventilation to disperse phenol odor and vapors. The following were used: pulse oximetry, non-invasive blood pressure, nasal plugging to avoid inhalational absorption of phenol, and cardiac monitoring to observe any signs of arrhythmias. Peripheral venous access was used for infusion of NS and drug intervention in case of possible incidents.

Sedation and analgesia scheme were as follows:
1 hour before the procedure ¿ 2 mg of lorazepam + association of oral 500 mg paracetamol/30 mg codeine during the procedure ¿ 2 g dypirone IV in the infusion of NS
For 24 hours ¿ alternating, every 4 hours, 100 mg of oral tramadol and the same paracetamol/codeine association.
The face was cleaned meticulously, with acetone-containing gauze, to remove any fat residue; this was followed by blockade in the medium pupillary line with 2% lidocaine, and phenol was applied with cotton swabs. Six cotton swabs were used per patient, one for each aesthetic unit of the face. When Baker’s formula was used, it was occluded for 48 hours with non-permeable tape.
After the procedure, patients remained under observation for 6 hours with cardiac monitor and pulse oximeter.
To evaluate the renal toxicity, phenol levels were determined 6 times by UGC: before, immediately after, and 6, 12, 24, and 48 hours after the procedure.
To evaluate the cardiac toxicity, a Holter monitor was used; it was placed on the patient 2 hours before beginning the procedure and removed after 24 hours. The following parameters were evaluated: minimal and maximal heart rate, baseline cardiac rhythm, presence of sustained supraventricular and ventricular tachycardia, atrial and ventricular PVCs, and changes in cardiac conduction and in the ST segment.
Laboratorial exams were repeated 7 and 30 days after the procedure.
Dermatological and clinical exams, as well as standardized photographic records, were performed on the 2nd, 7th, and 21st days, and 1, 3, 6, and 12 months after the procedure.
Groups were compared using analysis of variance or, in those cases in which data distribution was not normal, the Kruskal-Wallis test. A level of significance of 0.05 was adopted.

RESULTS

Forty-four female patients, aged from 40 to 66 years old finished the study; 11 were in G1, 13 in G2, 10 in G3, and 10 in G4. Sixteen patients were not included in the study for different reasons: irregularities in collecting urine samples, technical flaws on Holter readings, and missing follow-up appointments.

Significant differences among pre- and post-treatment laboratorial exams were not observed.

Urine gas chromatography showed fast urinary phenol elimination, with a half-life of 6 to 8 hours. Renal function, evaluated by laboratorial exams up to the 30th day and clinical signs up to one year, did not change. According to the UGC, when Baker’s formula is used, phenol is absorbed more rapidly than in other forms (chart), presenting a higher peak than the other peelings studied. After 48 hours, urine phenol levels returned to baseline levels (20.0 mg/g) in all groups.

On the Holter, changes in cardiac rhythm, ST segment, and conduction disturbances were not observed, and all patients remained in normal sinus rhythm after the peelings.

All cases showed an increase in heart rate, which was more important in G2, G3, and G4. Sustained ventricular tachycardia, present in 1 patient in G1, 1 in G3, and 2 in G4, which ceased immediately without medical intervention, was the most important cardiac change. Atrial and ventricular premature beats were present in all groups, but they were always asymptomatic and of short duration.

For the following parameters: age, minimal, medium, and maximal heart rate, presence of supraventricular tachycardia or sustained ventricular tachycardia, and supraventricular and ventricular premature contractions, a p value > 0.05 was obtained, showing a non-statistically significant difference among the four groups analyzed.

As for the time interval among facial aesthetic units, a statistically significant difference was seen among the four groups (p = 0.001).

DISCUSSION

The debate on the use of phenol for facial peelings is old. From the 1940s5 to nowadays,1 one can find studies comparing both sides of this drug: the excellent results of cutaneous applications and the serious risks resulting from its systemic absorption and toxicity.

Investigative studies on toxicity are old, and we proposed an update on the subject. It is known that the absorption of phenol into the bloodstream after its application is intense and fast, totaling 70% of the volume applied in 30 minutes; ¾ of this volume is metabolized by the liver and eliminated by the urine. In 1953, Ruedemann and Deichmann8 confirmed this fast penetration and elimination of phenol after being applied to human skin, by studying its serum levels after the application of topical lotions that contained 2%, 4.75%, and 10.86% of this drug. In 1971, Piotrowski, using phenol solutions at 5%, 10%, and 25%, evaluated the absorption of its vapors through the lungs and skin, and its urinary excretion, concluding it was completely eliminated within 24 hours.9

One of the objectives of this work was to study the urinary metabolism of phenol, using UGC, a colorimetric method that determines the urinary levels of phenol with specificity and sensitivity,10 for 48 hours after the peelings. In our patients, UGC showed fast urinary phenol elimination, with a half-life of 6 to 8 hours, and all groups presented normal levels after 24 to 48 hours. It should be emphasized that phenol is normally present in human urine, and its baseline levels correspond to 20.0 g/ml.

Our observations also showed that in G4, in which Baker’s formula was used, the urinary levels of phenol showed more elevated absorption peaks when compared to other groups. Until 2000, several authors1,11,12 believed that phenol penetration on human skin was inversely proportional to its concentration. They argued, against all chemical principles, that phenol in concentrations higher than 80% would have a keratocoagulation effect that would precipitate epidermal proteins, forming a barrier that would prevent deep dermal penetration; however, if diluted to 50%, it became a keratolytic, breaking the xxx bridges and increasing its penetration.19 After the studies of Hetter,13,14 we came to understand that the croton oil present in Baker’s formula deepens the peeling, allowing phenol to be absorbed into the bloodstream through the deep dermal plexus. Our observations corroborated those concepts, since we observed that in our patients, comparing the UGC of groups 1 and 4, phenol in Baker’s formula had greater absorption than in G1 although both had a 50% concentration.

Therefore, as for the liver and kidney complications that are supposedly related to phenol, we concluded that, in theory, they can occur, since those pathways participate in its metabolism and excretion, and there are no reports in the literature on this fact.10

However, it is well-known that the absorbed phenol can produce myocardial irritability,6,15 becoming the most worrisome factor in the context of the systemic toxicity generated by this drug.

The symptoms of cardiotoxicity reported more often in the literature include: tachycardia, bigeminism, and premature contractions, which can progress to ventricular tachycardia and atrial fibrillation.6,16 According to Truppman & Ellenby, cardiac toxicity manifests in sensitive patients, initially as tachycardia and premature contractions, progressing to atrial fibrillation in severe cases.16

In 1981, Litton, in a study among 587 dermatologists and plastic surgeons who used peelings with 50% phenol and 0.8% croton oil, found that 87% of the physicians reported that their patients did not present systemic complications, while 13% noticed tachycardia (6%), arrhythmias (1%), and increased blood pressure (0.3%).17

In those studies, patients were always evaluated by electrocardiographic records, which were limited to the intra- and immediate postoperative periods. With the use of the Holter monitor, those records could be extended to 24 hours. This method is commonly used to detect changes in heart rhythm in patients with suggestive symptoms of arrhythmia, to detect the causes, in which frequency and complexity can be quantified and related to the clinical symptoms, or to document the efficacy of the anti-arrhythmic therapy. In our patients, we observed an increase in heart rate in all cases, which was more important in G2, G3, and G4, asymptomatic atrial and ventricular PVCs in all groups, and sustained ventricular tachycardia in 4 patients of G1, G3, and G4, but which reverted spontaneously, without treatment, coinciding with the findings of Stagnone.18 Considering all parameters examined, except the application interval among facial units, the four groups analyzed showed no statistically significant differences, which leads to the conclusion that variations in concentration and depth of the peelings do not influence cardiac toxicity. This seems to be due to an unpredictable individual susceptibility. This finding corroborates the findings of Gross, who studied 43 patients and demonstrated that there is no apparent relationship between the serum level of phenol and the development of cardiac arrhythmias.19

Several authors1,4,5,6,15 agree that absorption and toxicity are primarily influenced by the extension of the skin exposed during a specific period of time, rather than by the concentration of phenol in the solution, and recommend monitoring, slow and spaced applications with the face divided in different areas, and forced diuresis as safety measures, but we had problems in all groups, even using slow applications.

In 1998, Stone referred to the myths about phenol: all or nothing, paleness, and uncontrollable toxicity, showing that there are still concerns associated with this drug.20

Although the time interval used on phenol applications does not change the parameters analyzed by the Holter, it is considered important to improve patient comfort, tranquility of the medical team, and greater safety regarding the development of arrhythmias.7

CONCLUSION

The dermatological surgeon should keep in mind that the use of phenol, although very useful, should be associated with several precautions: it is a toxic compound, which is absorbed by the skin, gaining access to the blood stream, and it is potentially capable of producing unpredictable cardiac complications that are independent of the concentration, type of application, and depth of skin affected.

References

1 . Matarasso SL. Phenol chemical peels. In: WHEELAND, RG. Cutaneous surgery. 1st ed. United States of America: Sauders. 1994;39:491-508

2 . Drake LA et al. Guidelines of care for chemical peeling. J Am Acad Dermatol. 1995;33:497-503

3 . Stajduhar-Caric Z. Acute phenol poisoning singular findings in a lethal case. Journal of Forensic Medicine. 1968;15:41-2

4 . Wexler MR et al. The prevention of cardiac arrythmias produced in an animal model by the topical application of a phenol preparation in common use for face peeling. Plast Reconstr Surg. 1984;73(4):595-8

5 . Deichmann WB. The distribuition, detoxification, and excretion of phenol in the mammalian body. Phenol Studies.1943;V:345-55

6 . Botta SA et al. Cardiac arrhythmias in phenol peeling: a suggested protocol for prevention. Aesthetic Plast Surg. 1998;12(2):115-7

7 . Warner MA, Harper JV. Cardiac dysrhythmias associates with chemical peeling with phenol. Anesthesiology. 1985;62:366-7

8 . Deichmann WB, Ruedemann R. Blood phenol level after topical application of phenol-containing preparations. J Am Med Assoc. 1953;152:506

9 . Piotrowski JK. Evaluation of exposure to phenol: absorption of phenol vapour in the lungs and through the skin and excretion of phenol in urine. Brit J Industr Med. 1971;28:172-8

10 . Bari EA. Determinação de fenol urinário por cromatografia gás-líquido no controle da exposição ao benzeno [dissertação]. São Paulo: Faculdade de Ciências Farmacêuticas, Universidade de São Paulo; 1984

11 . Stuzin MJ. Phenol peeling and the history of phenol peeling. Clinics in Plastic Surgery. 1998;25(1):1-19

12 . Glogau RG, Matarasso SL. Chemical peels trichloroacetic acid and phenol. Dermatol Clinics. 1995;13(2):263-76

13 . Hetter GP. An examination of the phenol-croton oil peel: part I. Dissecting the formula. Plast Reconstr Surg. 2000;105(1):227-39

14 . Hetter GP. An examination of the phenol-croton oil peel: part IV. Face peel results with different concentrations of phenol and croton oil. Plast Reconstr Surg. 2000;105(3):1081-3

15 . Litton, C. Observations after chemosurgery of the face. Plastic Reconstr Surg. 1963;32(5):554-6

16 . Truppman ES, Ellenby JD. Major electrocardiographic changes during chemical face peeling. Plastic Reconstr Surg. 1979;63(1):44-8

17 . Litton C, Trinidad G. Complications of chemical face peeling as evaluated by a questionnaire. Plast Reconstr Surg. 1981;67(6):738-43

18 . Stagnone GJ, Orgel MG, Satagnone JJ. Cardiovascular effects of topical 50 % trichloroacetic acid and Baker’s phenol solution. J Dermatol Surg Oncol. 1987;13(9):99-1002

19 . Gross BG. Cardiac arrhythmias during phenol face peeling. Plast Reconstr Surg. 1984;73(4):590-4

20 . Stone PA. The used of modified phenol for chemical face peeling. Clinics in Plastic Surgery. 1998;25(1):21-44

21 . Landau M. Advances in deep chemical peels. Dermatology nursing 2005;17:438-41


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