Treatment With Propranolol for Infantile Hemangioma in 13 Taiwanese Newborns and Young Infants

Background:Hemangioma in infants has a benign self-limited course, but the 10% of cases withcomplications need further treatment. Successful treatment with propranolol in western countries has been reported over the past few years. We evaluated the efficacy of propranolol fortreating infantile hemangioma in Taiwanese newborns and young infants.

Methods:Patients below 1 year of age treated with propanolol between November 2009 and March 2011 were enrolled. Demographic data, clinical features, imaging findings, treatmentregimens of propranolol, and outcome were investigated.

Results:Thirteen patients were treated with propranolol at a dose of 2e3 mg/kg/day. Seven(53.8%) patients had solitary hemangioma and six had multiple ones. The indications for treatment were risk of local event in nine patients, functional risk in four, local complication in one,and life-threatening complication in one. The median age for starting propranolol was 4months (range: 1e11 months). Responses to propranolol, such as decolorization, regressionin tumor size, or improvement of hemangioma-associated complications were observed inall patients within 1e2 weeks after treatment. Propranolol-associated adverse effectsoccurred in two patients. One infant had occasional tachypnea, and the other had occasionalpale-looking appearance. The symptoms resolved after dosage tapering.

Conclusion:Propranolol may be a promising therapeutic modality for infantile hemangioma.Therapeutic strategies are needed to evaluate the optimal treatment protocol and longterm adverse effects.

Copyright©2012, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. All rightsreserved.

1. Introduction

Infantile hemangioma (IH) is the most common benignvascular tumor of infancy, and its onset usually beginsduring the neonatal period. The incidence is estimated at4e5%1and is higher in girls and premature infants.2IHclassically manifests as a rapid proliferation phase in thefirst year after birth, followed by a spontaneous involutionphase that lasts for several years.3It usually has a selflimited course with minimal sequelae, and the mainstayof therapy is conservative observation. However, eventransient cosmetic disfigurement during the long involutionphase frequently induces psychological stress in theaffected children and their parents.4Moreover, approximately 10% of IH cases need further intervention due tolocal or life-threatening complications.5,6Some IH cancause local complications such as ulceration, pain,bleeding, scarring, secondary infection, and permanentdisfigurement. Others may cause significant functionalimpairment, vital organ compromise, or life-threateningcomplications. For these complicated IH cases, systemiccorticosteroids are generally considered to be the first-lineof pharmacological therapy. Although there is a 78-89%response rate,7a high recurrence rate of up to 36% andadverse effects limit its use.8Alternative therapeuticoptions, such as vincristine,9interferona,6and cyclophosphamide,10are used for steroid-refractory and criticalpatients, but their potential toxicities are a major concern.The dramatic response to propranolol in the treatmentof IH was first described by Le´aute´-Labre`ze et al11in 2008,and a number of successful cases have been reportedworldwide.12To the best of our knowledge, the efficacy ofpropranolol in Taiwanese hemangioma patients has notbeen evaluated. We investigated the therapeutic effect ofpropranolol in 13 Taiwanese newborns and young infantswith IH at a tertiary pediatric medical center.

2. Patients and Methods

In this retrospective observational study, we reviewed datafrom Taiwanese patients, aged<1 year, diagnosed with IHand treated with propranolol between November 2009 andMarch 2011. Demographic data, clinical features, results ofimaging for IH, propranolol dosage, treatment outcome,and complications were collected from medical charts.

Before initiation of propranolol treatment, comprehensive history taking, vital signs, and physical examinationswere performed in all patients to confirm that there wasno associated medical history or contraindications forpropranolol, such as past cardiopulmonary disease, hyperactive airway disease, asthma, sinus bradycardia,secondary or third-degree heart block, cardiogenic shock,and allergy to propranolol. Treatment regimens andpotential adverse effects of propranolol were explained tothe families of the patients. Informed consent forpropranolol treatment and use of the patients’ photographswas obtained from their parents.

The patients were first treated with 0.5e1 mg/kg/daypropranolol divided into two or three doses, and weeklyfollow-up at the outpatient clinic was arranged. At eachclinic visit, baseline heart rate was recorded and thedosage of propranolol was doubled to a maximum of2e3 mg/kg/day as tolerated. Parental education included:(1) observation for tachypnea, wheezing, symptoms andsigns of hypoglycemia, and signs of poor perfusion; (2)advice on taking the drugs with or after a meal to avoidhypoglycemia; (3) monitoring of heart rate and withholdingdrugs in the event of bradycardia, defined as a heart rate<100 beats/minute,13and signs of poor perfusion; (4)withholding drugs temporarily with acute illness; and (5)making a note of any possible propranolol-associateddiscomfort. During the stable course of treatment,monthly outpatient clinic follow-up was arranged. When IHhad regressed and flattened sufficiently, propranolol wasgradually tapered over 1 month by halving the dosage eachweek.

3. Results

Thirteen patients treated with 2-3 mg/kg/day propranololwere identified between November 2009 and March 2011.The demographic data, clinical features, imaging findings,and treatment outcomes of these patients are summarized in Table 1. There was a predominance of female (10/13,76.9%) and premature (7/13, 53.8%) infants among thepatients. Seven patients (53.8%) had solitary hemangioma,whereas the other six had multiple ones. The onset of IH in12 patients (92.3%) occurred in the neonatal period. Thesehemangiomas were located on the trunk (6/13, 46.2%),extremity (4/13, 30.8%), face (3/13, 23.1%), scalp (3/13,23.1%), liver (2/13, 15.4%), retro-orbital, intracranial areaand ethmoid sinus (1/13, 7.7%), neck (1/13, 7.7%), hardpalate (1/13, 7.7%), and external auditory meatus (1/13,7.7%). No patients had thrombocytopenia, consumptivecoagulopathy or KasabacheMerritt syndrome.

The indications for treatment in our patients weredivided into four categories: (1) risk of local complication,defined as high risk of local complication due to frequentfriction or scratching, in nine patients (69.2%,Figure 1A, 1Band 1E); (2) functional risk, defined as impairment of vision,hearing, feeding, or motility caused by IH, in four patients(30.8%,Figure 1C-1E); (3) local complication in one patient(7.7%, painful ulceration and secondary infection withPseudomonas aeruginosaof hemangioma over the left hand, fever, and leukocytosis in Patient 2,Figure 1F); and(4) life-threatening complication in one patient (7.7%, highoutput heart failure with respiratory distress due to largemultifocal hepatic hemangioma in Patient 3).

Diagnostic imaging studies were performed in 10 patients.Ultrasonography in eight patients revealed a mass withvisible or enriched blood flow. Multi-detector computedtomography in Patient 3 revealed diffuse hypervasculartumors over the liver (Figure 2A and 2B). Two tumors causedsignificant arteriovenous shunting. Magnetic resonanceimaging in Patient 4 showed a huge lobulated mass over theleft orbital cavity, left ethmoid sinus, left anterior skullbase, and left posterior aspect of the suprasellar cistern(Figure 2C-2E).

The median age for starting propranolol treatment was 4months, ranging from 1 to 11 months. Patients 3 and 9 weretreated with 2 mg/kg/day prednisolone for 1 week and 3weeks, respectively. The former patient was administeredwith propranolol due to progression of hemangiomaassociated heart failure, whereas the latter was shifted topropranolol due to progressive growth of hemangioma. Forthe other 11 patients, propranolol was the sole treatment.Immediate therapeutic response of superficial cutaneoushemangiomas to propranolol, manifested as decolorizationand regression in tumor size, was observed in all patientswithin 1e2 weeks after treatment. These cutaneous hisunderwent further regression under current propranololtreatment.

The median age for starting propranolol treatment was 4months, ranging from 1 to 11 months. Patients 3 and 9 weretreated with 2 mg/kg/day prednisolone for 1 week and 3weeks, respectively. The former patient was administeredwith propranolol due to progression of hemangiomaassociated heart failure, whereas the latter was shifted topropranolol due to progressive growth of hemangioma. Forthe other 11 patients, propranolol was the sole treatment.Immediate therapeutic response of superficial cutaneoushemangiomas to propranolol, manifested as decolorizationand regression in tumor size, was observed in all patientswithin 1e2 weeks after treatment. These cutaneous hisunderwent further regression under current propranolol treatment.

Therapeutic effects of propranolol on deep or visceral IHwere also seen in three patients. Patient 3 had multifocalhepatic IH, and signs of heart failure resolved after 1 weekof treatment. The patient was weaned off continuouspositive airway pressure support after 13 days. Serialultrasonography was used for follow-up and revealed thatthe size of the multifocal tumor had regressed after 3months of treatment, and only heterogenic echogenicityover the liver without nodular lesions was noted after5 months. Patient 4 had left retro-orbital IH, and after 1day of treatment, lagophthalmos improved. After 4 days,there was also an improvement in proptosis. Treatment with 3 mg/kg/day propranolol was maintained. Dosage wastapered at 7 months after treatment, but relapse withaggravation of proptosis was noted 1 week later. Afterrestarting the previous dosage of 3 mg/kg/day propranolol,proptosis improved again.

Six patients completed the treatment course, witha median treatment duration of 5.5 months (range: 3-14months) (Table 1). No recurrence of IH was noted in any ofthese patients during follow-up (range: 1-8 months). Sevenpatients continued to receive the treatment, with a medianduration of 5 months (range: 3-12 months).

Propranolol-associated adverse effects were suspectedin two patients (15.4%). Patient 3 had occasional tachypneaat 3 months after treatment. Patient 6 had occasional palelooking appearance at 1 month after treatment. Thesesymptoms resolved after propranolol dosage reduction. Nopatient was reported to have bradycardia with poorperfusion, and neither hypoglycemia nor hypotension wasobserved.

4. Discussion

Propranolol is a nonselectiveb-blocker and is usually usedin children for treating cardiac dysrhythmias, hypertension,congestive heart failure, tetralogy of Fallot, thyrotoxicosis,and migraine headache.14In 2008, Le´aute´-Labre`ze et alused propranolol to treat obstructive hypertrophic myocardiopathy in a young infant with coexisting nasal IH, andthe hemangioma regressed rapidly and serendipitously.11The dramatic efficacy was replicated in the other 10infants in the same trial and in another 21 infants withsevere hemangiomas in a large follow-up observationalstudy.15Propranolol was equally effective for treatment of superficial cutaneous IH as well as for deep or visceralIH.16e18Rapid tumor regression within days in infants withsevere or life-threatening hemangiomas has been demonstrated in several recent studies.12,19e23In addition,propranolol has been shown to be effective in cases withIH resistant to conventional treatment with high-dose corticosteriods, vincristine, cyclophosphamide, or interferona χ.

Our study showed that the onset of IH was usually inthe neonatal period and all patients had received propranolol treatment during the proliferation phase of IH. Bothsuperficial cutaneous and visceral hemangioma weredramatically responsive to propranolol treatment, which wasconsistent with the findings of previous studies.Insuperficial IH, decolorization and regression in tumorsize occurred within 1-2 weeks after treatment. In visceralor deep IH, the hemangioma-associated complicationsimproved within 1 week. All of our IH patients continued toshow tumor regression under propranolol treatment, or werestabilized after discontinuation of treatment.

The exact mechanism of propranolol action on IHremains to be clarified. It has been speculated that threedifferent pharmacological mechanisms of propranolol leadto early, intermediate and long-term effects on IH.26Earlyeffects are ascribed to decreased release of nitric oxideand subsequent vasoconstriction. Intermediate effects arebelieved to result from the blocking of angiogenesisfactors, including vascular endothelial growth factor, basicfibroblast growth factor, and matrix metalloproteinase 2and 9. Long-term effects of propranolol are thought to becaused by the induction of apoptosis in proliferatingcapillary endothelial cells. Another possible mechanism ofpropranolol-induced accelerated involution proposed byItinteang et al involves the reduction in expression ofcomponents of the renineangiotensin system, especiallyrenin and angiotensin II.

The optimal duration of propranolol treatment in IHhas yet to be established. It is reasonable to maintainpropranolol treatment after the first year of life when theproliferation phase is usually completed.20,21Some investigators have evaluated the effects of discontinuation ofpropranolol before the first year of age, when IH hadcompletely resolved.15,19Recurrence of IH in a few patientswas reported,15,18,19especially with abrupt withdrawal ofpropranolol.23However, reintroduction of propranolol forrecurrent growth of IH was still effective in most patients.19In our study, four patients completed the treatment courseof propranolol before the first year of age and two discontinued propranolol after the proliferation phase.Although no recurrences of IH were noted in all ourpatients, larger studies are required to determine how longthe treatment should be continued.

To date, no documented death or serious cardiovascularevent has been reported for children under 6 years of age asa direct result ofb-blocker exposure.14A few case reportshave described adverse effects of propranolol treatmentfor IH, including hypoglycemia,wheezing,15transienthypotension,15,19,20asymptomatic and transient bradycardia,and hyperkalemia.31Except for one preterminfant with potential life-threatening hyperkalemia,other adverse effects have been shown to resolve withoutspecific therapy. In our study, the patient with occasionaltachypnea after propranolol treatment had no subsequentrespiratory distress or desaturation even though thetachypnea was thought to be related to propranololinduced bronchospasm. Another patient had occasionaland transient pale-looking appearance with no signs of poorperfusion. Thus, the side effects found in our patients were not serious. Compared with conventional agents such assystemic corticosteroids, vincristine, and interferona,propranolol is a safer drug at the therapeutic dosage for IH.However, more clinical trials are needed to provide a guidefor better monitoring of hemodynamics, blood glucose andelectrolyte status in infants with IH during the treatmentperiod, to prevent potential adverse effects.

Propranolol use in IH is a promising therapeutic optionwith few complications. Randomized controlled studiesare necessary to determine the appropriate patient populations, treatment dosage, treatment duration, and longterm prognosis, as well as to investigate any long-termadverse effects of propranolol.