307V 50 16 2013infantile tumor with a frequency of 410 1Recentl - PDF document

307V 50 16, 2013infantile tumor, with a frequency of 4-10% [1].Recently, there has been an interest in propranololPropranolol may be more effective and safer than R E V I E WR E V I E WR E V I E WR E V I E WR E V I E WAAAAARRRRRTTTTTIIIIICCCCCLLLLLEEEEE 308V 50 16, 2013NFANTILEANTILEPathophysiologyIH are clonal expansions of endothelial cells. Geneticmutations in angiogenesis-related protein expressionhave been identified [5]. Characteristic features of IHinclude elevated expression of alkaline phosphatase,factor VIII antigen, and cluster of differentiation 31.dysregulated angiogenesis [6]. The overexpression ofglucose transporter 1 (GLUT-1) is specific to IH and is-1) is specific to IH and isIH Treatment Patterns and ModalitiesTreatment for IH may be necessary to a) prevent orthreatening complications. Accepted treatments includecryotherapy, laser ablation and surgical excision [1].gical excision [1].several corroborative reports, propranolol therapy wasfurther investigated in a twenty-patient randomizedcontrol trial (RCT) [9].Mechanism of ActionActiondependent cytotoxic effect on cultured hemangiomapathway, leading to decreased secretion of VEGF [11]. InGLUT-1 [12], though no study has evaluated thismodulation of stem-cell differentiation [11].We conducted a search on PubMed using combinationsof search terms “propranolol”, “hemangioma”, “beta-blocker,” and “beta-antagonist.” All relevant publicationsBibliographies of relevant articles were investigated. Wereported trial methodology, dosing and investigations, IHlocalizations, follow-up data, and adverse effects fromRCTs, case series, and case reports. Levels of evidencewere determined using Oxford criteria (www.cebm.org).Studies were assessed for bias.Table). Mos

t investigators did not specify duringinvestigator examined the efficacy of propranolol afterthe proliferative phase [14]. A few investigators included few investigators includedPatients with bronchial asthma were generally excluded.Most investigators increased drug dose to the target overget overtreatment at the target dose [13,15, 25-27]. Some studiesassess IH regression [9,13,15, 23, 25, 28]. Treatment wasresolution. A few investigators followed dose-tapering few investigators followed dose-taperingdiscontinuation to monitor for rebound growth. ToA summary of the larger studies in the literature isWeb TablePropranolol reduces color intensity, size and thickness of, size and thickness ofulcerated IH [18, 26]. Propranolol has been documentedto resolve IH resistant to steroid treatment [4,8,15-19].Hepatic hemangioma. Propranolol has been documentedto resolve hepatic IH [16]. Therapy can be initiated when 309V 50 16, 2013NFANTILEDosing Protocol•Oral suspension produced by dissolving 10 mg tablet in 5 mL of water•Inpatient monitoring for first six hours•Incremental dosage increase: Dosing strategy: 1 mg/kg/day for one week, then increase to 2-3•Target daily dose administered as three divided doses.Parent Education•Common side effects: Bradycardia, hypoglycemia, hypotensionTherapeutic Approachs•As a first line therapy in cutaneous variants•As a part of multimodal approach (surgery and/or steroids)Indications for Propranolol Therapy in Infantile Hemangioma•Non-resolution of IH•Failure of other treatments•IH location inaccessible to surgery and/or parents unwilling for surgery•Obstruction of airway, visual axis, or other vital structures•Severe cosmetic disfigurement•Severe ulcertation, existence of deep component, or oth

erwise locally complicated•Intolerance to other therapies, i.e. deranged liver function tests•Initial review by pediatric surgeon•Cardiovascular examination (blood pressure, heart rate, echocardiogram, electrocardiogram)•Blood count; Prothrombin time, and partial thromboplastin time•Blood urea nitrogen, creatinine; Liver function tests; Electrolytes•Repeat measurement and/or serial photography of hemangioma to assess response•Assessment of change in size and color, decrease in ulceration and inflammation•Maximal follow up interval 2 weeks in intial period of treatment for dose adjustment, monitoring and education•Intervals can be extended up to 1 month towards end of therapy•Repeat imaging•Discontine when IH has been static for 2 weeks or when regressed/resolved for 2 weeks.•Taper by serial halving to discontinue•Pediatric surgical consultation for counseling, reassurance and surgical intervention  Suggested management approach to infantile hemangioma.oach to infantile hemangioma.Propranolol in hepatic IH has been used as late as 10months after birth [29].Orbital hemangioma. Propranolol treatment isefficacious in the majority of orbital IH [4], occasionally 310V 50 16, 2013NFANTILEANTILESubglottic hemangioma. Favorable reports in laryngealFavorable reports in laryngealis required to monitor tumor regression.Other hemangiomas. Propranolol has successfullyresolved retroperitoneal [32] and mediastinal [33]hemangiomas. In reported outcomes in children withPHACE syndrome, propranolol caused significant yetincomplete reduction of IH [3,34-37]. The response toThe response tovessels should be undertaken before treatment todetermine the risk of cerebral ischemia [3].Limitations. Complete treatment failure has beendocum

ented [3,31]. IH may undergo rebound growthgo rebound growthAdverse EffectsAdverse effects include hypoglycemia, bradycardia,hypotension, and airway hyperreactivity. In an RCT,adverse effects [9]. Hypoglycemia may occur secondaryfects [9]. Hypoglycemia may occur secondaryA list of side effects attributed to propranolol use inPreterm infantsPropranolol was reported to be effective in a seriescomprised of seven preterm infants. No side effects,fects,in a series that included six preterm infants [41]. Another34 weeks of gestation. Two infants in these series had a fallin blood pressure within the first six hours of therapy,,Other beta-blockersAcebutolol, nadolol and timolol may provide similarefficacy to propranolol in IH treatment. Acebutolol hasbeen used in treatment of subglottic IH [31]. Topicaltimolol has been effective for cutaneous [20] and ocularfective for cutaneous [20] and oculareasier to administer than propranolol.Combined propranolol and corticosteroidsoidsreport, two children with airway-obstructing IH weretreated with combined prednisolone and propranolol.After 24 hours, both children were relieved of stridor andsteroid was discontinued [45]. These reports suggest thattherapy may provide a valid therapeutic approach tootherwise difficult-to-treat IH.Propranolol and surgeryPropranolol may limit the need for surgery in IH. In awith propranolol required surgery, whereas 29% of thosetreated with steroids required surgery [22]. Surgery stillneed urgent treatment [35]. Presumably, in patients withmay limit the extent of surgery necessary for an easy andSSOCIATEDETAACardiacdiacHypotension [13, 20, 21, 28]Tachycardia [22]achycardia [22]Insomnia [13]Drowsiness [18, 23, 24, 30, 38]Crying episodes/Anxiety [30]Hypot

onia [23]PulmonaryWheezing [13, 20, 24]Stridor [15]tridor [15]Gastrointestinal 311V 50 16, 2013NFANTILEANTILEIntralesional drug injection also causes regression ofperiorbital IH [47]. The use of a 1% ointment applied forcase series [40]. Topical treatments may result in feweradverse effects.Most reviewed studies provided level 4 evidence. Theyevaluate the efficacy of treatment.We have suggested a tentative treatment regimen (should be made on a case-by-case basis [48]. The child’sage, history of prematurity, hemangioma subtype andunderstanding should be considered. AbdominalPHACE syndrome should undergo cerebral angiography toinclude discussion of the warning signs of hypoglycemiaregular feeding schedule. A pediatric surgical opinionpossibility of surgical excision if therapy fails. In addition,effectively following propranolol therapy. SpecialMerritt syndrome. Regression of IH should be monitoredby serial photography. The above protocol should beevaluated by randomized, large-scale trials.ge-scale trials.challenges of assuring patient compliance andmaintaining close follow-up in India, it is inadvisable topromote propranolol therapy except in cases wherecareful and close monitoring of patient parameters isfeasible.Propranolol can be tried as first-line therapy in IHirrespective of age, location, extent and phase of growth.Treatment might also be helpful in downgrading the sizeamenable to surgical excision. Due to the lack of long-term side effects and its high response rate, propranololpediatricians and pediatric surgeons in order to establishits efficacy conclusively.: NG: designed and conceptualized the study,analyzed and interpreted the data in the study, and drafted themanuscript. SR: conceptualized the study,

drafted and revisedthe data. JXS: conceptualized the study, interpreted the data inthe study and revised the manuscript. All authors gave finalCompeting interests1.Frieden IJ, Haggstrom AN, Drolet BA, Mancini AJ,2.Young AZ, Cohen BA, Siegfried EC. Cutaneous Taeusch HW, Ballard RA,3.Manunza F, Syed S, Laguda B, Linward J, Kennedy H,4.Cheng JF, Gole GA, Sullivan TJ. Propranolol in the5.Yu Y, Varughese J, Brown LF, Mulliken JB, Bischoff J.6.Takahashi K, Mulliken JB, Kozakewich HP, Rogers RA,7.North PE, Waner M, Mizeracki A, Mihm MC, Jr. GLUT1:8.Leaute-Labreze C, Dumas de la Roque E, Hubiche T,9.Hogeling M, Adams S, Wargon O. A randomized 312V 50 16, 2013NFANTILE10.Bingham MM, Saltzman B, Vo NJ, Perkins JA.11.Greenberger S, Bischoff J. Infantile Hemangioma-12.Egert S, Nguyen N, Schwaiger M. Contribution of alpha-13.Sans V, de la Roque ED, Berge J, Grenier N, Boralevi F, Propranolol for severe14.Zvulunov A, McCuaig C, Frieden IJ, Mancini AJ, Puttgen15.Bagazgoitia L, Torrelo A, Gutierrez JC, Hernandez-Martin16.Marsciani A, Pericoli R, Alaggio R, Brisigotti M, Vergine17.Mistry N, Tzifa K. Use of propranolol to treat multicentric18.Hermans DJ, van Beynum IM, Schultze Kool LJ, van de19.Muthamilselvan S, Vinoth PN, Vilvanathan V, Ninan B,20.Blatt J, Morrell DS, Buck S, Zdanski C, Gold S, Stavas J,21.Holmes WJ, Mishra A, Gorst C, Liew SH. Propranolol as22.Price CJ, Lattouf C, Baum B, McLeod M, Schachner LA,23.Rossler J, Schill T, Bahr A, Truckenmuller W, Noellke P,haemangioma is superior to corticosteroid therapy - a24.Schupp CJ, Kleber JB, Gunther P, Holland-Cunz S.25.Celik A, Tiryaki S, Musayev A, Kismali E, Levent E,26.Saint-Jean M, Leaute-Labreze C, Mazereeuw-Hautier J,et al.27.Talaat AA, Elbasiouny MS, Elgendy DS, Elwakil

TF.Propranolol treatment of infantile hemangioma: clinicaland radiologic evaluations. J Pediatr Surg. 2012;47:707-28.Bertrand J, McCuaig C, Dubois J, Hatami A, Ondrejchak29.Mazereeuw-Hautier J, Hoeger PH, Benlahrech S,30.Schiestl C, Neuhaus K, Zoller S, Subotic U, Forster-31.Blanchet C, Nicollas R, Bigorre M, Amedro P, MondainM. Management of infantile subglottic hemangioma:32.Vanlander A, Decaluwe W, Vandelanotte M, Van Geet C,33.Fulkerson DH, Agim NG, Al-Shamy G, Metry DW,34.Haider KM, Plager DA, Neely DE, Eikenberry J,35.Leboulanger N, Cox A, Garabedian EN, Denoyelle F.36.Hernandez-Martin S, Lopez-Gutierrez JC, Lopez-37.Mohanan S, Besra L, Chandrashekar L, Thappa DM.Excellent response of infantile hemangioma associated38.Chai Q, Chen WL, Huang ZQ, Zhang DM, Fan S, Wang 313V 50 16, 2013NFANTILE39.Holland KE, Frieden IJ, Frommelt PC, Mancini AJ, Wyatt40.Kunzi-Rapp K. Topical propranolol therapy for infantile41.Moehrle M, Leaute-Labreze C, Schmidt V, Rocken M,42.Erbay A, Sarialioglu F, Malbora B, Yildirim SV, Varan B,43.Ye XX, Jin YB, Lin XX, Ma G, Chen XD, Qiu YJ, et al.Ye XX, Jin YB, Lin XX, Ma G, Chen XD, Qiu YJ, et al.infantile hemangiomas: a prospective study]. ZhonghuaZheng Xing Wai Ke Za Zhi. 2012;28:161-4.44.Koay AC, Choo MM, Nathan AM, Omar A, Lim CT.45.Rosbe KW, Suh KY, Meyer AK, Maguiness SM, Frieden46.Nunn A, Shah U, Ford J. Giving propranolol tablets to47.Awadein A, Fakhry MA. Evaluation of intralesional48.Lawley LP, Siegfried E, Todd JL. Propranolol treatment49.Qin ZP, Liu XJ, Li KL, Zhou Q, Yang XJ, Zheng JW.Qin ZP, Liu XJ, Li KL, Zhou Q, Yang XJ, Zheng JW.propranolol: evaluation of short-term efficacy and safety].Zhonghua Yi Xue Za Zhi. 2009;89:3130-4.50.Buckmiller LM, Munson PD, Dyamenahalli U, Dai Y