consenso uso propanololpediatrics 2013 drolet 128 40

DOI: 10.1542/peds.2012-1691; originally published online December 24, 2012; 2013;131;128Pediatrics

J. FriedenIlonaM. Kwon, Kari Martin, Jonathan Perkins, Dawn H. Siegel, Robert J. Boucek and

Blei, Eulalia Baselga, Laura Cassidy, David H. Darrow, Shawna Joachim, Eun-KyungKatherine B. Puttgen, Marcia Seefeldt, Robert Sidbury, Kendra M. Ward, Francine Leonardo Liberman, Susan MacLellan-Tobert, Anthony J. Mancini, Denise Metry,Bauman, Yvonne E. Chiu, Robert H. Chun, Maria C. Garzon, Kristen E. Holland,

Beth A. Drolet, Peter C. Frommelt, Sarah L. Chamlin, Anita Haggstrom, Nancy M.Consensus Conference

Initiation and Use of Propranolol for Infantile Hemangioma: Report of a

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located on the World Wide Web at: The online version of this article, along with updated information and services, is

of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2013 by the American Academy published, and trademarked by the American Academy of Pediatrics, 141 Northwest Pointpublication, it has been published continuously since 1948. PEDIATRICS is owned, PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

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Initiation and Use of Propranolol for InfantileHemangioma: Report of a Consensus Conference

abstractInfantile hemangiomas (IHs) are common neoplasms composed of pro-liferating endothelial-like cells. Despite the relative frequency of IH andthe potential severity of complications, there are currently no uniformguidelines for treatment. Although propranolol has rapidly been adop-ted, there is significant uncertainty and divergence of opinion regard-ing safety monitoring, dose escalation, and its use in PHACE syndrome(PHACE = posterior fossa, hemangioma, arterial lesions, cardiac ab-normalities, eye abnormalities; a cutaneous neurovascular syndromecharacterized by large, segmental hemangiomas of the head and neckalong with congenital anomalies of the brain, heart, eyes and/or chestwall). A consensus conference was held on December 9, 2011. Themultidisciplinary team reviewed existing data on the pharmacologicproperties of propranolol and all published reports pertaining to theuse of propranolol in pediatric patients. Workgroups were assignedspecific topics to propose protocols on the following subjects: contra-indications, special populations, pretreatment evaluation, dose esca-lation, and monitoring. Consensus protocols were recorded duringthe meeting and refined after the meeting. When appropriate, pro-tocol clarifications and revision were made and agreed upon by thegroup via teleconference. Because of the absence of high-qualityclinical research data, evidence-based recommendations are not pos-sible at present. However, the team agreed on a number of recom-mendations that arose from a review of existing evidence, includingwhen to treat complicated IH; contraindications and pretreatmentevaluation protocols; propranolol use in PHACE syndrome; formula-tion, target dose, and frequency of propranolol; initiation of propran-olol in infants; cardiovascular monitoring; ongoing monitoring; andprevention of hypoglycemia. Where there was considerable contro-versy, the more conservative approach was selected. We acknowledgethat the recommendations are conservative in nature and anticipatethat they will be revised as more data are made available. Pediatrics2013;131:128–140

AUTHORS: Beth A. Drolet, MD,a Peter C. Frommelt, MD,b

Sarah L. Chamlin, MD,c Anita Haggstrom, MD,d Nancy M.Bauman, MD FACS FAAP,e Yvonne E. Chiu, MD,f Robert H.Chun, MD,g Maria C. Garzon, MD,h Kristen E. Holland, MD,f

Leonardo Liberman, MD,i Susan MacLellan-Tobert, MD,j

Anthony J. Mancini, MD,c Denise Metry, MD,k Katherine B.Puttgen, MD,l Marcia Seefeldt, RN,m Robert Sidbury, MD,n

Kendra M. Ward, MD MS,o Francine Blei, MD,p EulaliaBaselga, MD,q Laura Cassidy, PhD,r David H. Darrow, MD,s

Shawna Joachim,f Eun-Kyung M. Kwon, BA,f Kari Martin,MD,f Jonathan Perkins, DO,b Dawn H. Siegel, MD,a Robert J.Boucek, MD,n and Ilona J. Frieden, MDt

aDepartments of Pediatrics, and Dermatology, bPediatricCardiology, fDermatology, gOtolaryngology, and rBiostatistics,Medical College of Wisconsin, Milwaukee, Wisconsin;cDepartments of Pediatrics and Dermatology, NorthwesternUniversity, Chicago, Illinois; dDepartments of Dermatology andPediatrics, Indiana University, Indianapolis, Indiana; eDepartmentof Otolaryngology, Children’s National Medical Center,Washington, District of Columbia; hDepartments of Dermatology,and Pediatrics, and iPediatrics, Columbia University, New York,New York; jDepartment of Cardiology, Gunderson LutheranHospital, La Crosse, Wisconsin; kDepartment of Dermatology,Baylor College of Medicine, Houston, Texas; lDepartment ofDermatology, Johns Hopkins Hospital, Baltimore, Maryland;mDepartment of Dermatology, Children’s Hospital of Wisconsin,Milwaukee, Wisconsin; nDepartments of Pediatrics, andCardiology, Seattle Children’s Hospital, Seattle, Washington;oDepartment of Pediatrics, Northwestern University, Chicago,Illinois; pDepartments of Hematology & Oncology, VascularBirthmark Institute of New York, New York, New York;qDepartment of Dermatology, Hospital de la Santa Creu I SantPau, Barcelona, Spain; sDepartments of Otolaryngology andPediatrics, Eastern Virginia Medical School, Norfolk, Virginia; andtDepartments of Dermatology & Pediatrics, University ofCalifornia San Francisco, San Francisco, California

KEY WORDSinfantile hemangioma, propranolol, PHACE syndrome,hypertension, bradycardia, hypoglycemia

ABBREVIATIONSBP—blood pressureECG—electrocardiogram, FDA, US Food and Drug AdministrationHR—heart rateIH—infantile hemangiomaPHACE—posterior fossa, hemangioma, arterial lesions, cardiacabnormalities, eye abnormalities

(Continued on last page)

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Infantile hemangiomas (IHs) are com-mon benign tumors composed of pro-liferating endothelial-like cells. Theduration and rate of growth are vari-able; some infants will have heman-giomas that grow very little, whereasothers grow rapidly and at an un-predictable rate. Althoughmost are notworrisome, ∼12% of IHs are signifi-cantly complex, requiring referral tospecialists for consideration of treat-ment.1,2 Complications of hemangiomas,for which systemic pharmacotherapy istypically initiated, include permanentdisfigurement, ulceration, bleeding, vi-sual compromise, airway obstruction,congestive heart failure and, rarely,death. Despite the relative frequency ofIH and the potential severity of compli-cations, uniform guidelines for treat-ment are lacking.

There are no US Food and Drug Ad-ministration (FDA)-approved agents forthe treatment of IH, and treatment iscurrently based on expert opinionand observational studies. Prospectivedata addressing the efficacy and safetyof any pharmacologic interventions forthe treatment of IH have not beengenerated, and available data areconfounded by the lack of a consensuson treatment criteria and objectiveoutcome measures. Agents with repor-ted activity in treating IH include corti-costeroids, interferona, vinca alkaloids,and, recently, propranolol.3–25

Since the initial report of propranololuse for the treatment of IH in 2008, therehasbeenaflurryofcasereportsandcaseseries describing its efficacy and po-tential side effects.3–6,10–15,18,21,23,24,26–36

These publications were not subjected tothe usual stringency of phase I/II/III clin-ical trials, and most were not pro-spective, randomized, or controlled. Withclinical use, propranolol has been foundto be rapidly effective for IH, well toler-ated, and better than previous therapiesat inducing regression. These observa-tions, coupled with the immediate avail-

ability of the medication in a pediatricformulation, have led to a rapid andwidespread adoption of propranolol forIH. Propranolol suspension is commer-cially available in the United States, butit does not currently have an FDA-approved indication for children. Car-diologists have historically used thismedication in infants with the diagnosisof supraventricular tachycardia. Incontrast to infants with supraventricu-lar tachycardia, for whom initiation ofpropranolol typically occurs in an in-patient setting with extensive cardiacmonitoring, the greatmajority of infantstreated for IH are cardiac healthy andare treated in an outpatient setting.Guidelines for dose initiation, dose es-calation, and toxicity monitoring werenever generated for use with IH; there-fore, each institution designed uniqueprotocols. These protocols vary consid-erably; some centers hospitalize allchildren for initiation of treatment,whereas others do so only rarely. Someexperts recommend intensive outpa-tient monitoring of patients, whereasothers do little to no monitoring.3

The distinct circumstances in whichpropranolol has become sowidely usedunderscores the importance of bring-ingmultiple specialties together to gainconsensus regarding dose initiation,safety monitoring, dose escalation, andits use in specific situations (eg, PHACEsyndrome).3 In this report, we reviewexisting data on the pharmacologicproperties of propranolol and all pub-lished reports pertaining to the useof propranolol in pediatric patients.With this review as the evidence base,

a multidisciplinary, multiinstitutionalexpert panel met in December 2011 todevelop a standardized, consensus-derived set of best practices for theuse of propranolol in infants with IH. Asmore information accumulates, it isexpected that this provisional set ofbest practices will change.

REVIEW

Pharmacologic Properties ofPropranolol

Propranolol is a synthetic, b-adrener-gic receptor-blocking agent that isclassified as nonselective because itblocks both b-1 and b-2 adrenergicreceptors. Chronotropic, inotropic, andvasodilator responses decrease pro-portionately when propranolol blocksthe b-receptor site, resulting in a de-crease in heart rate (HR) and bloodpressure (BP). Propranolol is highlylipophilic and undergoes first-passmetabolism by the liver with only∼25% of oral propranolol reaching thesystemic circulation. Multiple path-ways in the cytochrome P450 systemare involved in propranolol’s metabo-lism, making clinically important druginteractions a potential issue (Table 1).

Propranolol had previously been usedin pediatric patients primarily for thetreatment or prevention of cardiacarrhythmias, hypertension, outflow ob-structions in congenital heart disease,and hypertrophic cardiomyopathy. Itsantihypertensive effects result fromdecreased HR, decreased cardiac con-tractility, inhibition of renin release bythe kidneys, anddecreasedsympathetic

TABLE 1 Drug Interactions

Increase Blood Levels/Toxicity Decrease Blood Levels/DecreaseEfficacy

Inhibitors of CYP2D6: Inducers of hepatic drug metabolism:Amiodarone, cimetidine (but not ranitidine), delavudin,fluoxetine, paroxetine, quinidine, and ritonavir

Rifampin, ethanol, phenytoin, andphenobarbital

Inhibitors of CYP1A2:Imipramine, cimetidine, ciprofloxacin, fluvoxamine, isoniazid,ritonavir, theophylline, zileuton, zolmitriptan, and rizatriptan

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tone. However, the mechanism of actionof propranolol on IH is yet to be clearlydefined. Some of the proposed hypothe-ses include vasoconstriction, decreasedrenin production, inhibition of angiogen-esis, and stimulation of apoptosis.37–39

Propranolol Use for IH

A comprehensive review of the litera-ture was undertaken to understandthe breadth of current clinical practice.A PubMed search cross-referencedwith Google Scholar last performedon December 7, 2011, using the searchterms “propranolol” and “hemangi-oma” yielded 177 articles. Of these, 115articles were written in English anddiscussed use in humans. Thirty addi-tional articles were excluded becausethey were nonapplicable or lacked suf-ficient clinical data. Eighty-five articles(including 1175 patients) were reviewedin detail.4,11,13,15,18,21,23,24,26–34,36–38,40–104

The majority of these publications in-cluded,5 patients, and nearly all wereretrospective reports. There was only 1prospective trial and 1meta-analysis.58,80

Nearly half (35/85; 41%)of thepublicationswere interim reports with patients stillundergoing treatment; therefore, ad-verse events may be underestimated.Although there was significant vari-ability in the details provided by eacharticle, the authors chose to be in-clusive to understand the breadth ofcurrent clinical practice.

Response to therapy was discussed in79 articles, and the definitions andmeasures of response varied widely,from “stabilization” to “complete re-sponse.” Fewer than 10 articlesattempted to quantify the degree ofinvolution.13,15,23,41,42,58 Positive re-sponse in all treated patients wasreported in 86% of publications; theremaining 14% discussed at least sometreatment failures. In total, 19 of 1175published patients were reported astreatment failures, suggesting a 1.6%treatment failure rate. This rate may be

underestimated because treatment fail-ures may not be as commonly reported.In publications with adequate data fromwhich to calculate age at initiation oftherapy, the mean age was 5.1 months,with a median age of 4 months.

Adverse Events of Propranolol inthe Pediatric Population

Although propranolol has been wellstudied inadults, observationsof itsusein infants and children, nearly 40 yearsin duration, have been mainly anec-dotal. There are no FDA-approved indi-cations for propranolol in pediatricpatients in the United States. There is 1active phase II/III Investigational NewDrug application (ClinicalTrials.govNCT1056341) for the use of propranololfor the treatment of IH. On the basis ofcase reports and case series, oralpropranolol appears to have a favor-able safety profile in children. Deaths oracute heart failure have been associ-ated with propranolol initiation only inthe settings of intravenous adminis-tration or drug overdose.105,106

Given the variability in study design andthe retrospective nature of most re-ports, the true incidence of adverse

events in IH population is difficult to as-certain. For example, routine screeningfor bradycardia was only documentedin 128 of 1175 (10%) of patients reported.Of the 85 articles, 48 (56%) reported nocomplications in any patient, althoughreports of complications with pro-pranolol usage increased over timefrom 2008 to 2011 (Table 2). The mostfrequently reported serious complica-tions were asymptomatic hypotensionor hypotension for which no additionaldetails were provided; pulmonarysymptoms related to direct blockade ofadrenergic bronchodilation; hypogly-cemia or hypoglycemic seizure; asymp-tomatic bradycardia; and hyperkalemia.The most commonly reported non-potentially life-threatening complica-tions were sleep disturbances includingnightmares, somnolence, cool or mot-tled extremities, diarrhea, and gastro-esophageal reflux/upset.

Bradycardia and Hypotension

As a b-blocker, propranolol decreasesHR and, in part, BP as a result of neg-ative chronotropic and inotropiceffects on the heart. Propranolol’seffects on BP and HR in children peak

TABLE 2 Complications Due to Propranolol in Hemangioma Patients

Complications Recorded No. of Patients/ TotalNo. of Patients inPapers ReportingComplication

Frequency (%) ofComplication AmongPapers ReportingSaid Complication

Overall Frequency(%) of Total of 1175Patients Reviewed

in 85 Papers

Asymptomatic hypotension orhypotension (unspecified)

33/228 14.5 2.8

Symptomatic hypotension 3/46 6.5 0.3Pulmonary symptoms(bronchoconstriction,bronchiolitis, wheezing,pulmonary obstruction,apneic episode)

16/201 8.0 1.4

Hypoglycemia 10/88 11.4 0.9Asymptomatic bradycardia orbradycardia (unknown)

11/126 8.7 0.9

Symptomatic bradycardia 1/2 50 0.1Sleep disturbance (includingnightmares)

44/326 13.5 3.7

Somnolence 26/220 11.8 2.2Cool or mottled extremities 20/225 8.9 1.7Diarrhea 9/53 17.0 0.8Gastroesophageal reflux diseaseor gastrointestinal upset

8/133 6.0 0.7



around 2 hours after an oral dose.47

The reported protocols for initial dose,dose titration, and prospective moni-toring were extremely variable andtherefore difficult to compare in a uni-form fashion. Three prospective stud-ies, although limited by small patientnumbers and significant missing data,provide useful information. During ini-tiation of propranolol for IH in infants,bradycardia (,2 SD of normal) andhypotension (, 2 SD of normal) afterthe first dose (2 mg/kg/day divided 3times daily) were infrequent andasymptomatic.47 Changes (z scores.2) in systolic BP from baseline oc-curred in 7%, 22%, and 13% at 1, 2, and3 hours postpropranolol dosing, re-spectively. For HR, there were nochanges in z scores from baseline .2at any time point measured. As a group,significant changes in BP occurred onlyat 2 hours.47 In 28 patients treated forIH with doses up to 4 mg/kg/day, bra-dycardia was not noted as a side ef-fect.59 In a separate study of 25 infantsby Schiestl and colleagues, HR wascontinuously monitored during sleepand transient bradycardia was repor-ted in 4/25 infants. Decrease in di-astolic BP,50th percentile was notedin 16 of 28 patients (57%) in 1 study, butonly 1 patient developed clinically rec-ognizable changes with cold extremi-ties and prolonged capillary refill.59

Hypoglycemia

Symptomatic hypoglycemia and hypo-glycemic seizures have been reportedin infants with IH treated with oralpropranolol (Table 3).59,61,63,64,86,88,90,107

These cases occurred in both new-borns and toddlers but were often as-sociated with poor oral intake orconcomitant infection. The mecha-nisms through which propranolol-induced hypoglycemia develops arenot completely understood. Non-selective b-blockers, such as pro-pranolol, may block catecholamine-induced glycogenolysis, gluconeogene- TA

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times

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SPECIAL ARTICLE



sis, and lipolysis, predisposing to hy-poglycemia. Most of the reportedpatients who developed hypoglycemiawere prescribed relatively low doses(1.25–2.0 mg/kg/day), suggesting thathypoglycemia associated with pro-pranolol may not be dose-dependent.Historically, the 1 reported pediatricfatality from an accidental overdose oforal propranolol had a documentedblood glucose level of 0 mg/dL, sug-gesting that hypoglycemia may be themost serious complication in chil-dren.106 Patients with IH may be at in-creased risk if they have received orare concomitantly receiving treatmentwith corticosteroids, because adrenalsuppression may result in loss of thecounterregulatory cortisol responseand increase the risk of hypoglyce-mia.88 Children, infants, and especiallypreterm infants appear to be at higherrisk for this hypoglycemia as theirglucose utilization rates are threefoldhigher in the fasting state and theirglycogen stores are lower.108

Clinical manifestations of hypoglycemiain infants can vary widely. Mild hypogly-cemia produces symptoms associatedwith counterregulatory epinephrine ac-tion, including sweating, shakiness,tachycardia, anxiety, and hunger. Withpropranolol-induced b-adrenergic block-ade, early symptoms may be masked.Therefore, because sweating is not typi-cally blocked by b-blockers, this maybe a more reliable symptom for diag-nosis. More severe hypoglycemia pro-duces symptoms of neuroglycopenia,including lethargy, stupor, poor feeding,seizures, apnea, loss of consciousness,and hypothermia.

Bronchospasm

Bronchial hyperreactivity, described aswheezing, bronchospasm, or exacer-bation of asthma/bronchitis, is a rec-ognized side effect of propranolol as theresult of its direct blockade of adren-ergic bronchodilation. Certainly, the

use of propranolol in the setting ofknown reactive airway disease mustbe considered cautiously. The devel-opment of bronchial hyperreactivity inthe setting of an acute viral illness inpatients on propranolol has necessi-tated temporary discontinuation oftherapy.59

Hyperkalemia

Hyperkalemia (without electrocardio-graphic changes) was reported in 2children on propranolol for IH.72,109 Thecause of the hyperkalemia is notknown, but the authors postulate that itwas tumor lysis from the large ulcer-ated IH combined with impaired po-tassium uptake into cells as the resultof b blockade. Dental caries have beenreported in 2 pediatric patients treatedwith propranolol, although this may berelated to the formulation of the sus-pension (if it contains sucrose). b-ad-renergic antagonism of salivary glandfunction resulting in decreased saliva-tion has also been postulated asa contributing factor.58,70

SURVEY OF PROPRANOLOL USEFOR IH

A survey was designed and was dis-tributed to established prescribers ofpropranolol in Fall 2011 for IH by DrsSarah L. Chamlin, Beth A. Drolet, Anita N.Haggstrom, and Anthony J. Mancini.

The response rate was 76%, and mostrespondents were pediatric dermatol-ogists (88%), academicians (84%), andexperienced clinicians with a mean of15.25 years in practice. Before startingpropranolol, the following studies wereobtained with the noted frequency:electrocardiogram (ECG; 81%), BP mea-surement(41%),echocardiogram(38%),and HR measurement (38%). Cardiologyconsultation was “always obtained” by34% of respondents and “never ob-tained” by 25%, with the remainder(41%) stating that they “sometimesobtained” such consultation. Seventeen

(53%) prescribers “always” or “some-times” admitted patients to the hospitalto initiate therapy, with only 3 of theseprescribers stating that they alwaysadmitted. The other respondents ad-mitting children did so under specialcircumstances, including young age(under 6–8 weeks), extreme pre-maturity, significant comorbidity, PHACEsyndrome, airway hemangioma, andpoor social situations. Most respond-ents (81%) started propranolol at 0.5 to1.0mg/kg per day, with a goal dose of 2.0mg/kg per day in 84% of patients. Dosingwas twice daily for 38% and 3 times dailyfor 47%, with the remaining 15% dosing3 times daily initially with a change totwice daily when the child was older (6–12 months of age).

CONSENSUS METHODS

A consensus conference was held inChicago, Illinois, on December 9, 2011.This conference was sponsored by theNational Institute of Arthritis andMusculoskeletal and Skin Diseases(1R34AR060881-01). Twenty-eight par-ticipants attended from 12 institutions,representing 5 specialties. Collectively,the group has treated .1000 infantswith propranolol for IH. Given theinconsistencies in current institutionalpolicies, consensus was difficult to ob-tain on all issues. Because of the espe-cially vulnerable patient population ofinfants aged 1 to 6 months, the groupchose to remain cautious in the ap-proach to these recommendations.Where there was considerable contro-versy, the more conservative approachwas selected until additional safety datacan be obtained.

Results of the survey were shared, andparticipants were asked to review allexisting literature on the use and ad-verse effects of propranolol in thetreatment of IH, PHACE syndrome, andother indications in the pediatric pop-ulation. These data were summarized,andworkgroupswereassignedspecific



topics to propose protocols on the fol-lowing subjects: contraindications,special populations, pretreatment eval-uation, dose escalation andmonitoring,and patient education. These protocolswere presented to the entire group anddebated using an iterative process(nominal group technique).110 Consen-sus protocols were recorded during themeeting, refined after the meeting, andresubmitted to the entire group fordiscussion by teleconference and elec-tronic review. Commentswere recordedand discussed, and when appropriate,protocol clarifications and revisionswere made and agreed on by the groupvia teleconference.

Because of the absence of high-qualityclinical research data, evidence-basedrecommendations are not possibleat the present time, and these are notAmerican Academy of Pediatrics–endorsed recommendations. However,the multidisciplinary team agreed ona number of recommendations thatarose from a review of existing evi-dence. It is acknowledged that, in manyareas, evidence is generally confined toexpert opinion, case reports, observa-tional or descriptive studies, and un-controlled studies. We acknowledgethat the following recommendationsare conservative in nature, and weanticipate that they will be revised asmore data are made available.

CONSENSUS RECOMMENDATIONS

When to Treat IH

Given the wide spectrum of disease andthe natural tendency for involution, thegreatest challenge in caring for infantswith IH is determining which infants areat highest risk for complications and inneed of systemic treatment. Medicalmanagement is highly individualized,and treatment with oral propranolol isconsideredin thepresenceofulceration,impairment of a vital function (ocularcompromise or airway obstruction), orrisk of permanent disfigurement. Before

the initiation of therapy, the potentialrisks of adverse effects are carefullyconsidered and weighed against thebenefits of intervention. A medical teamwith expertise in both the managementof IH and the use of oral propranolol ininfantsprovidesthemostoptimalcaretopatients inneedof systemic therapywithpropranolol.

Contraindications andPretreatment History

Before initiatingpropranolol therapy forIH, screening for risks associated withpropranolol use should be performed.Relative contraindications are listed inTable 4. The prescribing physicianshould perform, or obtain documenta-tion of, a recent normal cardiovascularand pulmonary history and examina-tion. Key elements of the history arepoor feeding, dyspnea, tachypnea, di-aphoresis, wheezing, heart murmur, orfamily history of heart block or ar-rhythmia. The examination should beperformed by a care provider with ex-perience in evaluating infants andchildren. The examination should in-clude HR, BP, and cardiac and pulmo-nary assessment.

Pretreatment ECG

Routine ECG screening before initiationof propranolol for hemangiomas hasbeen advocated, although the utility ofECG screening for all children withhemangiomas before initiation of pro-pranolol therapy is unclear. In the fu-ture, a more indication-driven ECGstrategy is likely to develop because theincidence of ECG abnormalities that

would limit propranolol use in childrenwith IH appears low.4,7,10,13,15,18,21,25,27,29

For example, congenital completeheart block is rare, with an estimatedprevalence of 1 in 20 000 live births,111

and this is most commonly associatedwith maternal connective tissue dis-ease.112 Consensus was not achievedon the use of ECG for all children withIH, but ECG should be part of the pre-treatment evaluation in any child when

1. the HR is below normal for age113:

� newborns (,1 month old), ,70beats per minute,

� infants (1–12 months old), ,80beats per minute, and

� children (.12 months old):,70 beats per minute.

2. there is family history of congenitalheart conditions or arrhythmias(eg, heart block, long QT syndrome,sudden death), or maternal historyof connective tissue disease.

3. there is history of an arrhythmiaor an arrhythmia is auscultatedduring examination.

Because structural and functionalheart disease have not been associatedwith uncomplicated IH, echocardiog-raphyasa routinescreening toolbeforeinitiation of propranolol is not neces-sary in the absence of abnormal clinicalfindings.

Propranolol Use in PHACESyndrome

PHACE syndrome (Online MendelianInheritance in Man database ID 606519)is a cutaneous neurovascular syn-drome present in one-third of infantswith large, facial hemangiomas; it ischaracterized by large, segmentalhemangiomas of the head and neck andcongenital anomalies of the brain,heart, eyes, and/or chest wall.114

Arterial anomalies of the headandneckare the most common noncutaneousmanifestation of PHACE syndrome, andacute ischemic stroke is a known

TABLE 4 Contraindications to PropranololTherapy

Cardiogenic shockSinus bradycardiaHypotensionGreater than first-degree heart blockHeart failureBronchial asthmaHypersensitivity to propranolol hydrochloride

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complication.115 Although the arterialanomalies are widely variable, infantswith PHACE syndrome believed to be athighest risk for stroke are those withsevere, long-segment narrowing ornonvisualization of major cerebral orcervical arteries in the setting of in-adequate collateral circulation, espe-cially when there are coexistingcardiac and aortic arch anomalies(Table 5).116 Theoretically, propranololmay increase the risk of stroke inPHACE syndrome patients by droppingBP and attenuating flow through ab-sent, occluded, narrow, or stenoticvessels. Furthermore, nonselectiveb-blockers, such as propranolol, havebeen shown to increase variability insystolic BP to a greater degree thanb1-selective agents, and labile BP isa known risk factor for stroke.117 Thereare 2 reports of acute ischemic strokein PHACE syndrome patients on pro-pranolol to date. Both patients wereconcomitantly on oral steroids and hadsevere arteriopathy.116 Cardiac andaortic arch anomalies are also com-monly seen in PHACE syndrome andrequire echocardiography to assessintracardiac anatomy and function.Propranolol administration in thesepatients should be managed in closeconsultation with cardiology.

Infantswith PHACE syndrome representa unique management challenge be-cause most affected infants have ex-tensive facial hemangiomas, with highrisk for both medical morbidities andpermanent facial scarring. Suchpatients are thus prime candidates forpropranolol therapy.4 The potentialbenefits of treatment must be weighedagainst the risks. The safe use of pro-pranolol in individuals with PHACE hasbeen described in several small casereports and case series, although noclinical trials have been conducted toassess the overall safety.27,115

It is recommended that infants withlarge facial hemangiomas at risk for

PHACE be thoroughly evaluated withMRI/magnetic resonance angiographyof the head and neck and cardiac im-aging to include the aortic arch beforeconsidering propranolol. If imagingresults place a patient into a higher riskcategory for stroke (Table 5), consul-tation and comanagement with neu-rology is appropriate. If the potentialbenefits of propranolol outweigh therisks, the consensus group recom-mends use of the lowest possible dose,slow dosage titration upward, closeobservation including inpatient hospi-talization in high-risk infants, and 3times daily dosing to minimize abruptchanges in systolic BP.

Formulation, Target Dose, andFrequency

Propranolol is currently commerciallyavailable in propranolol hydrochlorideoral solution (20 mg/5 mL and 40 mg/5mL). It is recommended that the20mg/5mL preparation be used because of thesmall volumes required for this in-dication. The consensus group recom-mends a target dose of 1 to 3mg/kg perday with most members advocating2 mg/kg per day, the median dosereported in the literature. Given thefact that dose escalation is requiredwith propranolol and that IH often re-spond rapidly to even low doses, physi-

cians will often use dose response todetermine an individual’s optimal targetdose. Dose escalation from a low start-ing dose is always recommended evenin the presence of inpatient monitoringas the initial cardiac response to b

blockade may be pronounced.

The consensus group advocates thatthe daily dose of propranolol be dividedinto 3 times daily dosing with a mini-mum of 6 hours between doses, bal-ancing considerations of safety,efficacy, and convenience.

Initiation of Propranolol in InfantsWith IH

Some facilities may have the resourcesand expertise to safely monitor allpatients in an outpatient setting, andsome practitioners continue to admitall infants. The following suggestionswere made regarding monitoring forpotential side effects while initiatingoral propranolol for the treatment ofproblematic IH (Fig 1). We acknowledgethat the data for safe outpatient initi-ation is mounting but still relativelylimited for this indication. The recom-mendations are age-dependent withpatients divided into 2 age groups.

Inpatient hospitalization for initiationis suggested for the following: Infants#8 weeks of gestationally correctedage, or any age infant with inadequate

TABLE 5 Imaging and Clinical Features and Stroke Risk in PHACE Syndrome



social support, or any age infant withcomorbid conditions affecting the car-diovascular system, the respiratorysystem including symptomatic airwayhemangiomas or blood glucose main-tenance.

Outpatient initiation with monitoringcan be considered for infants andtoddlers older than 8 weeks of gesta-tionally corrected age with adequatesocial support and without significantcomorbid conditions.

Cardiovascular Monitoring

ThepeakeffectoforalpropranololonHRand BP is 1 to 3 hours after adminis-tration. Patients should be monitoredwith HR and BP measurement at base-line and at 1 and 2 hours after receivingthe initial dose, and after significantdose increase (.0.5 mg/kg/day), in-

cluding at least 1 set of measurementsafter the target dose has been ach-ieved. If HR and BP are abnormal, thechild should be monitored until the vi-tals normalize. Dose response is usu-ally most dramatic after the first dose;therefore, there is no need to repeatcardiovascular monitoring multipletimes for the same dose unless thechild is very young or has comorbidconditions affecting the cardiovascularsystem or the respiratory system in-cluding symptomatic airway heman-giomas. Bradycardia is important torecognize because the accurate mea-surement of BP in infants may bechallenging. HR is simple to measure,and normative data for inappropriatebradycardia have been established asfollows:

� Newborns (,1 month old), ,70beats per minute

� Infants (1–12 months old), ,80beats per minute

� Children (.12 months old),,70 beats per minute

SystolicBPvariessignificantlybetween1monthand6monthsofage,sonormativedata are difficult to interpret. Moreover,mostpediatricnormativeBP tablesweredesigned to evaluate for hypertension,not hypotension, and are based onauscultatory measurements.118 Oscillo-metric devices are convenient andminimize observer error, but they do notprovide measures that are identical toauscultation. Obtaining accurate BPmeasurements in neonates and infantsmay be challenging, and BP measure-ments should be obtained by experi-enced personnel. The infant should be ina warm room and in a resting state,awake or asleep. The use of an appro-priately sized infant cuff is essential. The

FIGURE 1(A) Summary of recommended dose initiation for inpatient scenario. (B) Summary of recommended dose initiation for outpatient scenario. PO, oral ad-ministration; q6, every 6; q8, every 8.

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inflatable portion of the cuff shouldencircle $75% of the limb circumfer-ence, and the length of the cuff shouldbe at least two-thirds of the length of theupper limb segment. Specific age-basednormative parameters for identificationof systolic hypotension in infants aredifficult to provide; as a general guide,we would describe systolic BP that isbelow normal (less than fifth percentileoscillometric or ,2 SD of normal aus-cultation)119 as follows:

� Newborn: ,57 mm Hg (,5th per-centile oscillometric) or 64 mm Hg(2 SD auscultation)

� 6 months: ,85 mm Hg (,5th per-centile oscillometric) or 65 mm Hg(2 SD auscultation)

� 1 year: ,88 mm Hg (,5th percen-tile oscillometric) or 66 mm Hg (2SD auscultation)

Patients who have HR and systolic BPmeasurements below these valuesduring propranolol initiation/dose es-calation warrant careful evaluation foradditional evidence of cardiovascularcompromise and should be consideredathigherrisk forcontinuedpropranololuse at that dose/continued dosage es-calation.

The inpatient and outpatient dose es-calation recommendations are age-dependent with patients divided into 2age groups, as shown in Fig 1.

Ongoing Monitoring

As discussed earlier, patients should bemonitored with HR and BP measure-ment at baseline and at 1 and 2 hoursafter a significant dose increase (.0.5mg/kg/day), including at least 1 set ofmeasurements after the target dosehas been achieved. There is no pub-lished information on the utility ofHolter monitoring in infants after ini-tiating propranolol to identify occultbradycardia or arrhythmias, and thisgroup has not reached consensus ona recommendation for Holter moni-

toring after reaching a steady dose.Most centers represented at the con-ference do not perform or recommendHolter monitoring in this setting ona routine basis.

Preventing Hypoglycemia

Although recognition of signs orsymptomsofhypoglycemiamaypromptearly intervention, measures should betaken to decrease the risk of hypogly-cemia. Because asymptomatic hypo-glycemia was not detected in studiesthat included a random serum glucoseas part of routine monitoring, and thetiming of hypoglycemic events, as out-lined in Table 3, has been variable andunpredictable, routine screening ofserum glucose is not indicated. Pro-pranolol should be administered dur-ing the daytime hours with a feedingshortly after administration. Parentsshould be instructed to ensure thattheir child is fed regularly and to avoidprolonged fasts. In otherwise healthychildren, the risk of hypoglycemia isage-dependent and begins after 8hours of fasting in children 0 to 2 yearsof age.47 Infants ,6 weeks should befed at least every 4 hours, between 6weeks and 4 months of age should befed at least every 5 hours, and .4months of age should be fed at least 6to 8 hours. Propranolol should be dis-continued during intercurrent illness,especially in the setting of restrictedoral intake. Children undergoing pro-cedures or radiologic imaging re-quiring fasting for sedation should besupported with Pedialyte (Abbott Nu-trition, Abbott Laboratories, Columbus,OH) or glucose-containing IV fluidsduring periprocedural periods. Pre-operative blood glucose levels mayidentify additional patients whosesymptoms might otherwise be maskedby preoperative medications and an-esthesia. Particular care should betaken in using propranolol in preterminfant, patients prescribed other med-ications known to be associated with

hypoglycemia or with medical con-ditions known to produce hypoglyce-mia.

CONCLUSIONS

Currently, the most significant barrierto the implementation of a multiin-stitutional clinical trial for the treat-ment of IH with oral propranolol is thelack of standardized toxicitymonitoringin infants without anatomic cardiac/vascular anomalies, as well as in in-fants with PHACE syndrome. Despitethe widespread use of this drug, no

TABLE 6 Consensus Meeting Key Learnings

• There are no FDA-approved indications forpropranolol in pediatric patients in theUnited States.

• There is significant uncertainty and divergence ofopinion regarding safety monitoring and doseescalation for propranolol use in IH.

• ECG should be part of the pretreatment evaluationin any child when the HR is below normal,arrhythmia is detected on cardiac exam, or thereis a family history of arrhythmias or maternalhistory of connective tissue disease.

• Cardiac and aortic arch anomalies are commonlyseen in PHACE syndrome and requireechocardiography to assess intracardiacanatomy and function in at-risk children.

• It is recommended that the 20 mg/5 mLpreparation of propranolol be used.

• The consensus group advocates that the dailydose of propranolol be divided into 3 times daily.

• Regardless of the setting in which propranolol isinitiated, it is recommended that the propranololdose be titrated up to a target dose, starting at 1mg/kg/day divided 3 times daily.

• The peak effect of oral propranolol on HR and BP is1 to 3 h after administration.

• Dose response is usually most dramatic after thefirst dose of propranolol.

• Bradycardia may be the most reliablemeasurement of toxicity because obtainingaccurate BPs in infants may be challenging, andnormative data for bradycardia are betterestablished.

• If a major escalation in dosage (.0.5 mg/kg/day)is indicated, the patient’s HR should be assessedbefore, 1 and 2 h after the increased dose isadministered.

• Hypoglycemia may be the most common seriouscomplication in children treated with propranololfor IH.

• Propranolol should be discontinued duringintercurrent illness, especially in the setting ofrestricted oral intake to prevent hypoglycemia.



systematic strategy currently exists toidentify toxicities of therapy for infantswith IH. The consensus team agreedon a number of recommendations thatarose fromareviewofexistingevidence

supplemented by expert opinion andclinical experience (Table 6). Theserecommendations will provide theplatform for large-scale phase II/IIIclinical trials to determine optimal

dosing regimens and long-term safetyprofiles. We anticipate that these guide-lines will be modified as more dataare made available from these futurestudies.

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Given the need for the multispecialty input, this was a highly collaborative process, and all authors have made substantial intellectual contributions to this article.Each author has met all three of the Pediatrics criteria. These authors drafted the initial manuscript (specific section in parenthesis) and approved the finalmanuscript as submitted. Drs Drolet (introduction), Frommelt (pretreatment evaluation), Chamlin (survey), Haggstrom (introduction), and Cassidy conceptualizedand designed the consensus conference program and grant award from the National Institutes of Health that supported the consensus conference. These authorsalso contributed to the acquisition of data by participating in person in the consensus meeting in Chicago and the iterative decision-making process, as well asseveral conference calls following the meeting. They drafted the initial manuscript and approved the final manuscript as submitted. Drs Frieden (conclusion),Boucek (adverse events), Bauman (proposed dosing regimen), Chiu (methods), Holland (hypoglycemia), Liberman (inpatient dose escalation), Ward (outpatientdose escalation), Metry (PHACE syndrome), and Puttgen (review of the hemangioma literature) contributed to the acquisition of data by participating in person inthe consensus meeting and the iterative decision-making process, as well as several conference calls following the meeting. Drs Chun, Garzon, MacLellan-Tobert,Mancini, Seefeldt, Sidbury, Blei, Baselga, Darrow, Joachim, Kwon, Martin, Perkins, and Siegel contributed to the acquisition of data and analysis and interpretationof data by participating in person in the consensus meeting in Chicago and the iterative decision-making process, as well as several conference calls following themeeting. These authors all critically reviewed 11 drafts of this manuscript and approved the final manuscript as submitted.

www.pediatrics.org/cgi/doi/10.1542/peds.2012-1691

doi:10.1542/peds.2012-1691

Accepted for publication Aug 31, 2012

Address correspondence to Beth A. Drolet, MD, Dermatology Department, 8701 Watertown Plank Rd, TBRC, 2nd Floor, Suite C2010, Milwaukee, WI 53226. E-mail:[email protected]

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2013 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The following authors disclose a conflict of interest consisting of involvement in the HEMANGIOL study, which was sponsored by PierreFabre: Drs Mancini, Sidbury, and Baselga. Drs Frieden and Baselga also disclose that they acted as consultants for Pierre Fabre. The other authors have indicatedthey have no financial relationships relevant to this article to disclose.

FUNDING: This work was supported by grant NIH-NIAMS-1R34AR060881-01 from the National Institutes of Health/National Institute of Arthritis and Musculoskeletaland Skin Diseases. Funded by the National Institutes of Health (NIH).


mailto:[email protected]


DOI: 10.1542/peds.2012-1691; originally published online December 24, 2012; 2013;131;128Pediatrics

J. FriedenIlonaM. Kwon, Kari Martin, Jonathan Perkins, Dawn H. Siegel, Robert J. Boucek and

Blei, Eulalia Baselga, Laura Cassidy, David H. Darrow, Shawna Joachim, Eun-KyungKatherine B. Puttgen, Marcia Seefeldt, Robert Sidbury, Kendra M. Ward, Francine Leonardo Liberman, Susan MacLellan-Tobert, Anthony J. Mancini, Denise Metry,Bauman, Yvonne E. Chiu, Robert H. Chun, Maria C. Garzon, Kristen E. Holland,

Beth A. Drolet, Peter C. Frommelt, Sarah L. Chamlin, Anita Haggstrom, Nancy M.Consensus Conference

Initiation and Use of Propranolol for Infantile Hemangioma: Report of a

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