Failure of Intralesional Propranolol in InfantileHemangiomas

Mauricio Torres-Pradilla, M.D.,* and Eulalia Baselga, M.D.†

*Pediatric Dermatology, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain, †Pediatric Dermatology,Clinica Dermatologica Dermik, Barcelona, Spain

Abstract: The purpose of this study was to evaluate the use ofintralesional propranolol injection in the management of small, noncom-plicated infantile hemangiomas (IHs) located in areas of cosmeticconcern. A prospective study was performed in six female infants withsmall, non-complicated IHs in areas of cosmetic concern. The parents hadrefused oral propranolol or the patients had no response to topical timololor had relapsed after oral propranolol and the parents refused furthersystemic treatment. All six patients were treated with 1 mg/mL propran-olol solution at a dose of 0.2 mL/cm2. The size, color, and growth of thehemangiomas were monitored and recorded every 4 weeks. Treatmentresponse was evaluated using a 5-point scale: much better (+2), better(+1), same (0), worse (�1), and much worse (�2). Heart rate and bloodpressure were measured before and 1 hour after each injection. Adverseeffects after medication were evaluated and managed accordingly. Allhemangiomas stopped growing during therapy, but no significantchanges in size or color were observed, even after repeated injections,and all patients were evaluated as 0 (same). One patient whose heman-gioma stopped growing during treatment presented rebound growth aftertherapy cessation. No changes in heart rate or blood pressure wereobserved after intralesional propranolol injection. Adverse effectsobserved were pain and redness after injection. Intralesional propranololseems safe but is not effective for the treatment of IH.

Oral propranolol therapy has revolutionized thenatural history of infantile hemangiomas (IHs).Despite the controversy over its safety, it is acceptedworldwide as the treatment of choice in large orcomplicated IH (1). In the treatment of small IHs thatdo not compromise any vital function but are located

in areas of cosmetic concern, a less invasive form oftreatment could be considered. Topical propranololand timolol have recently been used in such cases, andboth treatments provide a good response in superficialIHs but a limited response in IHs with a significant,deep component (2–5).

Address correspondence to Mauricio Torres-Pradilla, M.D.,Pediatric Dermatology, Hospital de la Santa Creu I Sant Pau,C/S. Antoni M Claret 167, 08025, Barcelona, Spain, ore-mail: m.torres@dermik.es.

DOI: 10.1111/pde.12175

© 2013 Wiley Periodicals, Inc. 1

CLINICAL AND LABORATORY INVESTIGATIONS

Pediatric Dermatology 1–3, 2013

When corticosteroids were used as the treatment ofchoice for IHs, they were administered as intralesionalinjections for smaller IHs in areas of cosmetic concernin an attempt to limit systemic exposure (6). A recentprospective clinical study concluded that intralesionalpropranolol was almost as effective as intralesionalsteroids in treating periocular IHs, and that it was notassociated with significant cardiovascular changes oradverse effects during or after injection (7).

The aim of the present study was to assess the useof intralesional propranolol injection in the treatmentof small, noncomplicated hemangiomas located inareas of cosmetic concern.

MATERIALS AND METHODS

The hospital ethics committee approved the protocolof this prospective study, which was carried outaccording to the Declaration of Helsinki. The parentsof all study patients gave their written informedconsent for inclusion in the study.

All patients presented IHs of less than 5 cm in sizein areas of cosmetic concern and treatment wasindicated. Inclusion criteria were that the parentshad refused oral propranolol or the patients had noresponse to topical timolol or had relapsed after oralpropranolol and the parents refused further systemictreatment. Data were collected from November 2011through April 2012.

Patients received an intralesional 1 mg/mL pro-pranolol injection. The volumes of injected drugdepended on the size of the lesion, at a dose of0.2 mL/cm, with a maximum volume of 1 mL. Thenumber of injections was determined according to theclinical response in each case. All patients werescheduled for 4-week follow-up visits. Serial photo-graphs were obtained at each visit and responses totherapy were evaluated on a 5-point scale by theevaluators and parents: much better (+2), better (+1),same (0), worse (�1), and much worse (�2). Heartrate and blood pressure were recorded before treat-ment and 30 minutes after treatment. Patientsremained at the hospital for 1 hour after injection.

RESULTS

Six patients were included in this study. The mean ageat first treatment was 7.3 � 4.3 months. All patientswere female. The mean dose of propranolol injec-tion was 0.4 mL. All IHs were focal. Three had asuperficial component and three were mixed. Themean size was 2 cm, and five IHs were located on theface. Table 1 summarizes the patient data.

At 1-month follow-up after the first injection, allIHs had stopped growing. Only one patient wasevaluated at this point as same (0) and no furtherinjections were given. The other five IHs showed aslight change in color and were evaluated as better(+1); a second injection was given.

After two injections, four of these five patientspresented no changes in their IHs. They were evalu-ated as same (0) and the treatment was stopped. In theremaining patient, patient 3, a slight change in colorwas noticed. It was decided to perform a thirdinjection, after which no further improvement wasobserved. Ten weeks after the last injection the IHsuffered a slight regrowth (Fig. 1 A, B).

The overall improvements in the three criteriaevaluated in each hemangioma—growth cessation,

TABLE 1. Summary of Data on Patients Treated withIntralesional Propranolol

Patientnumber 1 2 3 4 5 6

Type of IH Su M M Su Su MLocalization Front Front Nasal

tipUpperlip

Chest Front

Previoustreatment

OP N N T N N

Age at starttreatment(mos)

9 12 3 2 6 12

Dose (mL) 0.2 0.4 0.2 0.2 0.6 0.4Number ofinjections

2 1 4 2 2 2

Adverseeffects

P, E P, E P, E P, E P P

Relapse No No Yes No No NoOverallevaluation

S S B S S S

Su, superficial; M, mixed; D, deep; OP, oral propranolol(propranolol suspension 2 mg/kg/day for 4 mos); N, none; T,topical timolol (timolol maleate 0.5% twice a day for 1 mo); P, pain;E, mild erythema; MB, much better; B, better; S, same; W, worse;MW, much worse.

A B

Figure 1. (A) Patient 3. HI located on the nasal tip beforethe first propranolol injection. (B) Results obtained afterthree injections, 12 weeks later.

2 Pediatric Dermatology 2013

color, and size—were negligible and the response tointralesional propranolol in all cases was same (0).

None of the patients developed significant changesin blood pressure or heart rate during or afterinjection. The only adverse events were local painand redness during and after injection, lasting nolonger than 5 minutes.

DISCUSSION

The decision to treat IH and the form of treatment iscomplex. In some cases the indication for systemictreatment with oral propranolol is clear despite thepotential side effects. In other cases, due to the naturalhistory of this disease, we sometimes doubt the needto treat them at all. Furthermore, most superficial IHsrespond to topical timolol. However, in the midst ofthese varied options, small, noncomplicated IHs thathave a mixed or deep component and are located inareas of cosmetic concern continue in a grey zone.

In the present study the only results obtained werethe cessation of growth of all the IHs duringtreatment. We did not observe any marked changesin color or size, suggesting that the cessation couldhave been due to the natural history of IH rather thanto the direct effect of the medication. In only patient 3did we consider that the cessation of growth was dueto propranolol injection, as a rebound in growth wasobserved after treatment cessation. Although weconsider it unlikely, it cannot be excluded that furtherimprovement may have been achieved in this patientwith further injections

Our findings do not agree with those in the onlyother clinical trial published to date concerningintralesional propranolol for the treatment of perioc-ular IH. The authors of the study in questionconcluded that the results obtained with a singleinjection of intralesional propranolol were similar tothose obtained with intralesional corticosteroids.

The results from our study suggest that althoughoral and topical propranolol have been used success-fully as a treatment for IH, the rate of effectivenessdecreases with intralesional administration. This ispossibly because the vehicle in this form was notappropriate for intralesional injection, leading toerratic absorption and no effect. We were unable todemonstrate this because we did not measure systemiclevels. Another theory for this therapeutic failure isthat the dose and number of injections was simply toolow although we calculated the doses based on a

previous clinical trial that reported successful results.Because we did not find any other studies investigat-ing intralesional propranolol, further research isrequired to resolve this discrepancy.

Another possible explanation for the lack of effectis that the patients’ mean age was 7.3 months.Because 80% of IHs have reached their final sizebefore 5 months of age, patients included could beconsidered “old” for this treatment although appre-ciable changes were not observed in the youngerpatients.

The only adverse effects observed—local pain andredness during and after injections—could beexplained by the low pH of the propranolol solution(approximate pH 3–3.5). However, although none ofthe patients included presented any local or systemicsequelae after treatment, further studies are needed toconfirm the safety and therapeutic effect of intrale-sional propranolol in IH.

CONCLUSIONS

Intralesional propranolol seems safe, but it does notappear to be effective in the treatment of non-complicated hemangiomas, even after repeated injec-tions. Although the hemangiomas in all of ourpatients stopped growing after the injection, thiscould also have been the result of the natural historyof IH.

REFERENCES

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3. Lawley LP, Siegfried E, Todd JL. Propranolol treatmentfor hemangioma of infancy: risks and recommendations.Pediatr Dermatol 2009;26:610–614.

4. Moehrle M, Leaute-Labreze C, Schmidt V et al. Topicaltimolol for small hemangiomas of infancy. PediatrDermatol 2013;30:245–249.

5. Xu G, Lv R, Zhao Z et al. Topical propranolol fortreatment of superficial infantile hemangiomas. J AmAcad Dermatol 2012;67:1210–1213.

6. Chen MT, Yeong EK, Horng SY. Intralesional cortico-steroid therapy in proliferating head and neck heman-giomas: a review of 155 cases. J Pediatr Surg2000;35:420–423.

7. Awadein A, Fakhry MA. Evaluation of intralesionalpropranolol for periocular capillary hemangioma. ClinOphthalmol 2011;5:1135–1140.

Torres-Pradilla and Baselga: Infantile Hemangiomas 3