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Off-label use of propranolol for infantile hemangioma requires watchful eye


Pediatric dermatologists are taking a very slow - but hopeful - approach to using propranolol to treat hemangiomas in children. In doing so, they are also carefully monitoring children for possible unwanted reactions such as hypotension, bradycardia and hypoglycemia.

Key Points

In doing so, they are also carefully monitoring children for possible unwanted reactions such as hypotension, bradycardia and hypoglycemia.

"We are being cautiously optimistic, but it is a really amazing revolution in how we treat these children," notes Kate Puttgen, M.D., F.A.A.D., assistant professor, departments of dermatology and pediatrics, Johns Hopkins University School of Medicine, Baltimore.

Off-label approach

Since the publication of those findings, many pediatric dermatologists are using propranolol off-label to treat infantile hemangiomas.

"Propranolol is considered unproven, and even though steroids are not FDA (Food and Drug Administration)-approved as a treatment, they are the de facto standard-of-care therapy," Dr. Puttgen says. "Some clinicians feel safe to be using both therapies in children."

Clinicians at Johns Hopkins University School of Medicine say propranolol is being administered as a first-line therapy at their institution for hemangiomas that require intervention, but that clinicians are eager to see more rigorous data to support their treatment choices.

Collaborative care

In particular cases, using both therapies yields a synergistic effect, Dr. Puttgen notes. When hemangiomas are threatening function - for example, when they are located in the airway - dermatologists work in collaboration with their otolaryngologist colleagues who prefer to see both therapies employed. "We usually taper them off steroids as quickly as we can," Dr. Puttgen says.

Dr. Puttgen notes doctors are seeing far fewer side effects in their patients since oral steroids have become second-line therapy at Johns Hopkins, but rigorous vigilance is practiced to ensure no serious adverse events occur with propranolol.

"Our primary concerns in monitoring are for occurrences of hypotension, bradycardia and masking the signs and symptoms of hypoglycemia," Dr. Puttgen says.

Robin Gehris, M.D., chief of pediatric dermatologic surgery and pediatric dermatologist at Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center (UPMC), notes that infants cannot communicate as adults would be able to if they were experiencing adverse events of hypoglycemia, hypotension or bradycardia. Unlike adults, who may complain of light-headedness or dizziness, infants may simply appear more fussy.

"A baby can't tell you that they are feeling light-headed or dizzy," Dr. Gehris says, adding that clinicians may interpret lethargy or non-responsiveness as a sign, although obviously late and undesirable, of hypoglycemia.

At Dr. Gehris' institution, active non-intervention with extremely close clinical follow-up has always been the initial choice in management of early, non-threatening infantile hemangiomas.

If an infantile hemangioma growth becomes aggressive or threatens to be form-threatening of function-threatening, Dr. Gehris' first-line intervention historically has been oral or intralesional steroids. More recently, propranolol has become her preferred first or second option of therapy.

"Steroids can result in a halting of future hemangioma growth; however, they very seldom cause active regression in a hemangioma," Dr. Gehris says.

Steroid side effects

In addition, long-term use of high doses of steroids makes it difficult for infants to stay on schedule with some of their vaccinations, since their immune systems are suppressed, Dr. Gehris says.

Infants who are treated with high doses of steroids often experience irritability as well as gastric irritation from the medication, and they can also develop a cushingoid appearance.

Both UPMC and Johns Hopkins use a similar inpatient protocol for propranolol administration, with 48-hour hospital admission of babies, performance of a baseline electrocardiogram, and close monitoring of vital signs such as blood pressure and heart rate. Blood glucose levels are measured periodically to rule out hypoglycemia.

Infants with PHACE syndrome, who may have concomitant cardiac abnormalities and/or aortic coarctation, are not suitable initial candidates for propranolol therapy.

"You have to be careful that you are giving the drug to a child who has perfect cardiac functioning," Dr. Gehris says.

Benefits of experience

As clinicians develop more experience and comfort with propranolol, and as larger, well-done trials of this therapy enter the literature that validate its safety, the length of hospital stay for infants who are receiving the therapy may decrease, according to Dr. Gehris.

Clinicians at UPCM initiate propranolol therapy with a dose of 0.17 mg/kg/dose, administer the same dose after that, and titrate the third dose. Infants are reassessed about a week after they have been discharged. At Dr. Puttgen's institution, clinicians initiate propranolol at 0.33 mg/kg/dose for doses one through three and increase to 0.67 mg/kg/dose for doses four through six.

What makes propranolol effective in treating infantile hemangiomas is open to speculation.

"It's safe to say that we don't know, at this point in time, the exact mechanism of action to explain how propranolol can cause a halt of growth and a true regression of some infantile hemangiomas," Dr. Gehris says. "There are many hypotheses right now, but none that have been fully elucidated in the laboratory model."

Dr. Puttgen notes that one theory is that there is a downregulation of a growth factor that is upregulated early in the proliferative phase of infantile hemangiomas, resulting in regression of the lesion.

"It looks like there is something vasoconstrictive in the hemangiomas," Dr. Puttgen says. "Over a 48-hour period, the hemangioma becomes softer to the touch and transforms from a reddish pink to a purple color. That is a good sign that the patient is responding to the propranolol."

Disclosures: Drs. Puttgen and Gehris report no relevant financial interests.

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