Infantile hemangiomas (IHs) are common neoplasms composed of proliferating endothelial-like cells. Despite the relative frequency of IH and the potential severity of complications, there are currently no uniform guidelines for treatment. Although propranolol has rapidly been adopted, there is significant uncertainty and divergence of opinion regarding safety monitoring, dose escalation, and its use in PHACE syndrome (PHACE = posterior fossa, hemangioma, arterial lesions, cardiac abnormalities, eye abnormalities; a cutaneous neurovascular syndrome characterized by large, segmental hemangiomas of the head and neck along with congenital anomalies of the brain, heart, eyes and/or chest wall). A consensus conference was held on December 9, 2011. The multidisciplinary team reviewed existing data on the pharmacologic properties of propranolol and all published reports pertaining to the use of propranolol in pediatric patients. Workgroups were assigned specific topics to propose protocols on the following subjects: contraindications, special populations, pretreatment evaluation, dose escalation, and monitoring. Consensus protocols were recorded during the meeting and refined after the meeting. When appropriate, protocol clarifications and revision were made and agreed upon by the group via teleconference. Because of the absence of high-quality clinical research data, evidence-based recommendations are not possible at present. However, the team agreed on a number of recommendations that arose from a review of existing evidence, including when to treat complicated IH; contraindications and pretreatment evaluation protocols; propranolol use in PHACE syndrome; formulation, target dose, and frequency of propranolol; initiation of propranolol in infants; cardiovascular monitoring; ongoing monitoring; and prevention of hypoglycemia. Where there was considerable controversy, the more conservative approach was selected. We acknowledge that the recommendations are conservative in nature and anticipate that they will be revised as more data are made available.
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January 2013
Special Article|
January 01 2013
Initiation and Use of Propranolol for Infantile Hemangioma: Report of a Consensus Conference
Beth A. Drolet, MD;
aDepartments of Pediatrics, and Dermatology,
Address correspondence to Beth A. Drolet, MD, Dermatology Department, 8701 Watertown Plank Rd, TBRC, 2nd Floor, Suite C2010, Milwaukee, WI 53226. E-mail: bdrolet@mcw.edu
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Peter C. Frommelt, MD;
Peter C. Frommelt, MD
bPediatric Cardiology,
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Sarah L. Chamlin, MD;
Sarah L. Chamlin, MD
cDepartments of Pediatrics and Dermatology, Northwestern University, Chicago, Illinois;
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Anita Haggstrom, MD;
Anita Haggstrom, MD
dDepartments of Dermatology and Pediatrics, Indiana University, Indianapolis, Indiana;
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Nancy M. Bauman, MD FACS FAAP;
Nancy M. Bauman, MD FACS FAAP
eDepartment of Otolaryngology, Children’s National Medical Center, Washington, District of Columbia;
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Robert H. Chun, MD;
Robert H. Chun, MD
gOtolaryngology, and
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Maria C. Garzon, MD;
Maria C. Garzon, MD
hDepartments of Dermatology, and Pediatrics, and
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Kristen E. Holland, MD;
Kristen E. Holland, MD
fDermatology,
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Leonardo Liberman, MD;
Leonardo Liberman, MD
iPediatrics, Columbia University, New York, New York;
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Susan MacLellan-Tobert, MD;
Susan MacLellan-Tobert, MD
jDepartment of Cardiology, Gunderson Lutheran Hospital, La Crosse, Wisconsin;
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Anthony J. Mancini, MD;
Anthony J. Mancini, MD
cDepartments of Pediatrics and Dermatology, Northwestern University, Chicago, Illinois;
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Denise Metry, MD;
Denise Metry, MD
kDepartment of Dermatology, Baylor College of Medicine, Houston, Texas;
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Katherine B. Puttgen, MD;
Katherine B. Puttgen, MD
lDepartment of Dermatology, Johns Hopkins Hospital, Baltimore, Maryland;
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Marcia Seefeldt, RN;
Marcia Seefeldt, RN
mDepartment of Dermatology, Children’s Hospital of Wisconsin, Milwaukee, Wisconsin;
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Robert Sidbury, MD;
Robert Sidbury, MD
nDepartments of Pediatrics, and Cardiology, Seattle Children’s Hospital, Seattle, Washington;
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Kendra M. Ward, MS;
Kendra M. Ward, MS
oDepartment of Pediatrics, Northwestern University, Chicago, Illinois;
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Francine Blei, MD;
Francine Blei, MD
pDepartments of Hematology & Oncology, Vascular Birthmark Institute of New York, New York, New York;
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Eulalia Baselga, MD;
Eulalia Baselga, MD
qDepartment of Dermatology, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain;
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Laura Cassidy, PhD;
Laura Cassidy, PhD
rBiostatistics, Medical College of Wisconsin, Milwaukee, Wisconsin;
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David H. Darrow, MD;
David H. Darrow, MD
sDepartments of Otolaryngology and Pediatrics, Eastern Virginia Medical School, Norfolk, Virginia; and
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Eun-Kyung M. Kwon, BA;
Eun-Kyung M. Kwon, BA
fDermatology,
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Jonathan Perkins, DO;
Jonathan Perkins, DO
bPediatric Cardiology,
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Dawn H. Siegel, MD;
Dawn H. Siegel, MD
aDepartments of Pediatrics, and Dermatology,
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Robert J. Boucek, MD;
Robert J. Boucek, MD
nDepartments of Pediatrics, and Cardiology, Seattle Children’s Hospital, Seattle, Washington;
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Ilona J. Frieden, MD
Ilona J. Frieden, MD
tDepartments of Dermatology & Pediatrics, University of California San Francisco, San Francisco, California
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Address correspondence to Beth A. Drolet, MD, Dermatology Department, 8701 Watertown Plank Rd, TBRC, 2nd Floor, Suite C2010, Milwaukee, WI 53226. E-mail: bdrolet@mcw.edu
FINANCIAL DISCLOSURE: The following authors disclose a conflict of interest consisting of involvement in the HEMANGIOL study, which was sponsored by Pierre Fabre: Drs Mancini, Sidbury, and Baselga. Drs Frieden and Baselga also disclose that they acted as consultants for Pierre Fabre. The other authors have indicated they have no financial relationships relevant to this article to disclose.
Pediatrics (2013) 131 (1): 128–140.
Article history
Accepted:
August 31 2012
Citation
Beth A. Drolet, Peter C. Frommelt, Sarah L. Chamlin, Anita Haggstrom, Nancy M. Bauman, Yvonne E. Chiu, Robert H. Chun, Maria C. Garzon, Kristen E. Holland, Leonardo Liberman, Susan MacLellan-Tobert, Anthony J. Mancini, Denise Metry, Katherine B. Puttgen, Marcia Seefeldt, Robert Sidbury, Kendra M. Ward, Francine Blei, Eulalia Baselga, Laura Cassidy, David H. Darrow, Shawna Joachim, Eun-Kyung M. Kwon, Kari Martin, Jonathan Perkins, Dawn H. Siegel, Robert J. Boucek, Ilona J. Frieden; Initiation and Use of Propranolol for Infantile Hemangioma: Report of a Consensus Conference. Pediatrics January 2013; 131 (1): 128–140. 10.1542/peds.2012-1691
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To the Editor:
We read with great interest the article titled "Initiation and use of propranolol for infantile hemangioma: report of a consensus conference" by Drolet et al.1 We appreciate the authors' extraordinary contribution which provides us with uniform guidelines for the therapeutic use of propranolol in infantile hemangiomas (IHs) and recommendations for further determination of optimal dosing regimes and long-term safety profiles of ? -blockers in the treatment of IHs. Nonetheless, there are 2 important unanswered questions remain and need further discussion.
First, when should we start propranolol treatment of IHs? Most IHs do not cause serious morbidities and the great majority of patients with IH will not need treatment. Accordingly, current belief supposing that most IH should be left untreated along a police of 'benign neglect' (or 'wait and see') was considered and is still firmly encountered in clinical practice.2 Unfortunately, a significant minority IH can cause permanent disfigurement or functional compromise. In addition, quality of life may be significant affect for both parents and affected individuals. Although propranolol treatment can be efficacious beyond the proliferative phase, irreversible skin changes may have already occurred. Furthermore, in cases of early propranolol treatments, a considerable shortening of the natural course of IHs could be achieved especially for those lesions at proliferative phase3. Therefore, for the IHs needing treatment, the ideal time to treat is before or as soon as evidence of permanent anatomic distortion or medical sequelae develops. A recent study by Tollefson et al4 demonstrated that the most dramatic growth of superficial IHs occur between 5.5 and 7.5 weeks, much earlier than previously appreciated. The authors of this study suggest the need for a paradigm shift in the timing of referral and initiation of treatment of high-risk IH so that therapy can be initiated before or early in the course of most rapid growth, rather than after it is already completed. We can anticipate that the age when treatment is initiated is likely to became lower as we become more aware of the use of propranolol as a highly effective treatment for IHs and become comfortable with it use in very young infants.
As we move on to define the ideal duration of propranolol treatment, a second question arises: when should we stop propranolol treatment of IHs? Although 80% IH growth occurs in the first 3 months, IHs with a significant subcutaneous component may continue to proliferate up to a year. Segmental IHs have been reported to continue to proliferate for even longer, to a mean age of 17 months.5 Many studies found that rebound or relapse occurred more frequently in patients who completed propranolol treatment before 1 year of age.2, 3 Therefore, the optimal propranolol treatment must at least cover the entire proliferative phase, which could be adjusted according to the IH subtype. On the other hand, for late propranolol treatments started after the end of proliferative phase of IHs, some authors suggest that propranolol treatment should be continued empirically until the maximal improvement has been achieved.2
References
1. Drolet BA, Frommelt PC, Chamlin SL, et al. Initiation and use of propranolol for infantile hemangioma: report of a consensus conference. Pediatrics. 2013; 131(1): 128-40.
2. Talaat AA, Elbasiouny MS, Elgendy DS, Elwakil TF. Propranolol treatment of infantile hemangioma: clinical and radiologic evaluations. J Pediatr Surg. 2012; 47(4): 707-14.
3. Hogeling M, Adams S, Wargon O. A randomized controlled trial of propranolol for infantile hemangiomas. Pediatrics. 2011; 128(2): 259-66.
4. Tollefson MM, Frieden IJ. Early growth of infantile hemangiomas: what parents' photographs tell us. Pediatrics. 2012; 130(2): 314-20.
5. Schiestl C, Neuhaus K, Zoller S, et al. Efficacy and safety of propranolol as first-line treatment for infantile hemangiomas. Eur J Pediatr. 2011; 170(4): 493-501.
Conflict of Interest:
None declared
We read with interest the report by Drolet et al. regarding propranolol for the treatment of infantile hemangiomas.(1) The authors are to be congratulated on a thorough review. However, several points deserve further discussion. First, Figure 1 incorrectly states that propranolol doses should be administered "q6 hrs," whereas it is clear from the text, Table 6, and the cited references that the dosing should be 3 times a day or every 8 hours. Second, we disagree that checking the blood pressure and heart rate at 1 and 2 hours after receiving the initial dose is indicated. As noted by the authors in Table 2, the reported frequency of symptomatic hypotension and bradycardia are 0.3% and 0.1%, respectively. It should be expected that propranolol would decrease both heart rate and blood pressure from baseline. Without clearer guidelines as to what constitutes intolerance, this recommendation has the potential to generate needless confusion, anxiety, unnecessary testing and even hospital admissions. In addition, it necessitates a separate clinic visit for the family, who would need to procure the propranolol from a pharmacy and return to clinic (almost certainly on another day) for administration of the first dose and monitoring. In our opinion, this places an unnecessary burden on the family. Finally, we recommend vigorous parental education, as implied by the authors but not specifically addressed. We have developed a one page parent-friendly handout which we review with the parent(s) when initiating propranolol. It contains contact information, a list of potential side effects to watch for, a reminder to feed the child around the time of each propranolol dose, and blank spaces for the clinician to write in the exact doses for each patient along with instructions on when to dose escalate. We also provide parents with oral syringes and review the exact dosing instructions with them using an empty syringe. These practices have been well received by parents, and can potentially reduce errors in dosing and administration.(2)
Thomas W. McLean, M.D. Wesley Covitz, M.D. Department of Pediatrics Wake Forest University School of Medicine Medical Center Boulevard Winston-Salem, NC 27157 tmclean@wakehealth.edu
References 1. Drolet BA, Frommelt PC, Chamlin SL, et al. Initiation and use of propranolol for infantile hemangioma: report of a consensus conference. Pediatrics. 2013;131(1):128-140. 2. Neuspiel DR and Stubbs EH. Patient safety in ambulatory care. Pediatr Clin North Am. 2012;59(6):1341-1354.
Conflict of Interest:
None declared
I read the article entitled "Initiation and use of propranolol for infantile hemangioma: report of a consensus conference" published in Pediatrics, 2013, 131(1):128-140 1 with great interest and got lots of valuable information. I am very grateful to all the experts who made great efforts to review the existing data and propose the current protocols on the use of propranolol for infantile hemangioma (IH). I agreed on a number of recommendations from the consensus conference, however, I feel that the recommended dose initiation both for inpatient and outpatient scenarios were a little complex and inconvenient to be applied, especially initiation of propranolol and subsequent dose escalation. After strict in vitro experimental study 2 and detailed discussion with Chinese colleagues with expertise in both the management of IH and the use of oral propranolol in infants, we proposed an outpatient protocol on the use of propranolol for IH as follows:
Oral propranolol (10mg/tablet) is initiated at a dose of 1 (infants below 2.5 months) to 2 (infants over 2.5 months) mg/kg per day 3, divided 2 times daily for one month. The dose is increased to 2 mg/kg per day (target dose) for infants below 2.5 months at the first visit, and remains 2 mg/kg per day (target dose) for infants over 2.5 months at the first visit. Medication is continued at home, and the patients are asked to revisit every month, with serial examinations, photography and monitoring of adverse effects. Treatment was discontinued when the response reached a plateau and the patient became older than 1 year 4. The dosage of oral propranolol was tapered during a 4-week period (to halve the dose for 2 weeks and to halve the dose further for the next 2 weeks and then stop) 5 to prevent rebound growth.
Until now, we have treated more than 150 patients with IH in the head and neck region using this protocol in our institution. Excellent results were obtained, and no serious adverse effects were found. We believe that this outpatient protocol is safe, effective and easily applied in clinic.
A typical case was herein presented. A 3-month old girl with hemangioma in her left lower lip was referred to our clinic. After careful examinations and a baseline cardiac evaluation, she was treated with oral propranolol at a dose of 2 mg/kg per day, divided 2 times daily on an outpatient basis. The treatment continued until the child was 11.5 months with no remarkable lesion. Propranolol was tapered over a period of 4 weeks. The patient revisited us at the age of 2 years and 10 months; the lesion regressed totally without any problem.
References
1. Drolet BA, Frommelt PC, Chamlin SL, et al. Initiation and use of propranolol for infantile hemangioma: report of a consensus conference. Pediatrics. 2013;131(1):128-140
2. Mai HM, Zheng JW, Wang YA, Yang XJ, Zhou Q, Qin ZP, Li KL. CD133 selected stem cells from proliferating infantile hemangioma and establishment of an in vivo mice model of hemangioma. Chin Med J (Engl). 2013;126(1):88-94
3. Qin ZP, Liu XJ, Li KL, Zhou Q, Yang XJ, Zheng JW. Treatment of infantile hemangiomas with low-dose propranolol: evaluation of short-term efficacy and safety. Zhonghua Yi Xue Za Zhi. 2009;89(44):3130-3134
4. Missoi TG, Lueder GT, Gilbertson K, Bayliss SJ. Oral propranolol for treatment of periocular infantile hemangiomas. Arch Ophthalmol. 2011;129(7):899-903
5. Manunza F, Syed S, Laguda B, Linward J, Kennedy H, Gholam K, Glover M, Giardini A, Harper JI. Propranolol for complicated infantile haemangiomas: a case series of 30 infants. Br J Dermatol. 2010;162(2):466-468
Conflict of Interest:
None declared