All infants brought to our hospital's pediatric dermatology clinic with hemangiomas between October 2008 and March 2011 were studied prospectively. The patients were followed until August 2011. We kept records on type of hemangioma, phase, location and distribution, size, color, and the presence or not of ulceration or other complications. In cases of head and neck hemangiomas with a segmental distribution or spanning the midline, imaging studies (nuclear magnetic resonance, nuclear magnetic resonance angiography, or ultrasound) and cardiac function and eye evaluations were ordered. Infants with periorbital hemangiomas were also examined by the ophthalmologist. Focal, deep, or mixed lesions and large hemangiomas (>5cm) were studied by Doppler ultrasound. Infants with multiple hemangiomas (5 or more) also underwent a liver ultrasound. Thyroid stimulating hormone level was determined in infants with multiple or large hemangiomas.

Since Leauté-Labrezze and coworkers2 first reported using propranolol for severe hemangiomas of infancy in 2008, many reports and other publications have attested to the benefits of this treatment,3,5,6,10,11,13–15 although few authors have analyzed more than 20 patients and hardly any have published prospective studies.6 Among recent Spanish publications, we single out those of Bagazgoitia and coworkers,14 who reported outcomes for 71 patients based on a multicenter retrospective design, and Bernabeu and coworkers,3 who provided a descriptive analysis of 28 cases. Our prospective study of a cohort of 20 infants aimed to evaluate the overall effect and safety of the outpatient treatment regimen we used and to explore factors that might influence the response of hemangiomas to propranolol.

The characteristics of our patients were similar to those generally described for infants with hemangiomas17 and are consistent with the patient profiles in other case series.14 Thus, most of our patients were females, and most of the vascular tumors were on the head or neck and were of focal distribution, superficial, and in the proliferative phase on evaluation. Treatment usually started when the infant was 2 to 3 months old; only 2 infant girls were older than 12 months of age when we started them on propranolol.

Most of our patients had not been treated previously, although 5 infants had been given corticosteroids, with no response. They were weaned from that medication.

Some of the infants in our series had several complications that would justify treatment, but we recorded only the principal reason for prescribing the drug. The largest group of patients (50%) were included in the interest of preventing nearby structures from becoming compromised by a rapidly growing hemangioma; risk of vital structural compromise was especially relevant in 4 infants with periocular involvement that interfered with eye opening (20%). Our inclusion of these infants is consistent with the current practice of treating high-risk hemangiomas with propranolol.18 Ulceration was the second most frequent reason for prescribing propranolol in this series.

Pretreatment cardiac assessment was unremarkable for most of our patients, but we did identify 2 infants with atrial septal defects and 1 infant with persistent ductus arteriosus. The cardiologist indicated that these findings did not rule out treatment with propranolol, however. Findings of nuclear magnetic resonance imaging and the ophthalmologist's evaluation were negative except for eye closure in some cases and retinal blood vessel tortuosity in 1 infant.

The daily dosage of 2mg/kg we used in this study is generally considered to provide a sufficient amount of the drug. Given the pharmacokinetics of propranolol, 3 doses per day are recommended. Some authors, however, have prescribed regimens of 3mg/kg/d,7 while others have started therapy with lower dosages and gradually increased the amount based on periodic evaluations.15,19 The dosage has even been doubled (to 4mg/kg/d) on observation of no response.3,15 It is important to point out that no oral propranolol preparation is commercially available for infants. An extemporaneously prepared formulation is therefore required. Our hospital's pharmacy department prepared the formulations for this study, so the concentration could be adjusted as the infant grew, ensuring that parents could give the correct dosage easily. The pharmacists used a sucrose-containing syrup with no added stabilizing agents, thus avoiding substances that might have triggered an allergic reaction or been toxic for such young patients. However, the best excipient for oral administration of this drug to infants has not yet been determined, and we note that incipient caries have been reported in relation to sucrose-containing formulations of propranolol.20 It is not known whether this β-blocker's effect of reducing salivation might also contribute to the development of caries.

There is clear consensus that cardiac performance should be evaluated before propranolol is started.12,14,16 A history of bronchial hyperreactivity is an exclusion criterion and blood sugar levels should be monitored at follow-up visits along with blood pressure and heart rate. Debate centers on the best way to monitor the infant taking propranolol. Some believe that the possibility of hypotension and bradycardia, particularly when large-volume or multiple hemangiomas are present, puts cardiac output at risk. Another concern that has been expressed is the risk of hypoglycemia,21 because of the possibility of permanent neurologic damage associated with this complication.6,21 These possible effects have led some to hospitalize the infant for 48hours and to start treatment with 0.16mg/kg/d and gradually increase the dosage to 2mg/kg/d if blood sugar levels and vital constants remain normal.9,19 However, long experience with large doses of propranolol in very young infants with congenital heart disease would not suggest that such an approach is necessary except during the first week of life, when the fragile neonatal condition would argue against prescribing this drug. Propranolol has been found safe even for infants with very low birthweights.22 Rare adverse events such as diarrhea23 or hyperkalemia24 have been described, but most series have observed few adverse effects, which have been of little clinical importance. Nonetheless, as this medication becomes more widely used, practitioners are usually advised to proceed with caution. We chose to treat our patients on an outpatient basis, as have other authors.5,8 We did not detect variations in blood sugar levels, such as hypoglycemia during treatment. In fact, this potential adverse event can be prevented by administering the drug with meals, avoiding starting treatment in infants less than 1 month old, and not prescribing concurrent treatment with oral corticosteroids, which can increase the risk of low blood sugar.21 It is advisable to educate parents on the possible signs of hypoglycemia so that they can take their child to a hospital if necessary.

Blood pressure—both systolic and diastolic—and heart rate stayed within normal age- and sex-adjusted ranges at all check-ups in all cases. An infant's blood pressure should be taken by a properly trained staff member to ensure that readings are accurate. The rate of weight gain was also within normal ranges for all our patients. An infant who was accidentally given a dose that was 8-fold higher than prescribed developed no problems.25 The risk that propranolol might trigger an asthma attack must be considered and treatment should be avoided or interrupted during episodes of bronchiolitis, as occurred in one of our patients. Propranolol would be formally contraindicated in cases of well-established asthma, when continuous use of bronchodilators would be required. The fact that half our patients with an excellent response to therapy had previously been treated with oral corticosteroids reflects the severity of the hemangiomas in our series.

We would like to emphasize that the outpatient regimen we used was effective and satisfactory and, as some authors have suggested previously, this approach might lower the hospitalization-related costs of this therapy.5

The effectiveness of the treatment regimen we used was excellent overall, and in no case did we observe a lack of response. Although the response evaluation system we used might have limitations, we can say that our observations are consistent with those reported from other studies that concluded that propranolol is effective for treating infantile hemangiomas. It is important to emphasize that no consensus has emerged on the best way to measure response criteria; thus, studies differ with regard to how many assessors are consulted (as many as 5 opinions have been recorded) or how color, size and other criteria are weighted.3,10,14 Our assessment system was similar to that of Bayleis and coworkers,26 although we required that 2 experts come to complete agreement and we also included parent satisfaction. We think it is important to take the parents’ perspective into consideration, although previous studies have not done so. Parent satisfaction is a key element in adherence to treatment and in cooperation with adequate follow-up. Perhaps consensus on this would be a goal experts might consider for the future.

We observed that in all cases of periorbital hemangioma, treatment led to rapid improvement in eye opening, consistent with reports from earlier studies11,14 and suggesting a good prognosis for vision in the affected eye. Case 1 (Fig. 1) was exemplary: the ophthalmologist detected retinal blood vessel tortuosity on initial examination of that infant but vessels were nearly normal on later evaluation. Other authors have also observed improvements in such eye defects or vision problems as microphthalmia or astigmatism.27 Treatment with propranolol in such cases would be quite clearly indicated, therefore, and this drug is in fact now considered a first-line treatment for hemangiomas that put the eye at risk.13 Nonetheless, we note that clinical response was minimal in an infant in our series who had an eyelid hemangioma and for whom treatment started late, at 17 months. The response of nasal hemangiomas in our series was very variable. In only 1 case was the outcome considered excellent (Fig. 2), whereas response was excellent for a scalp hemangioma (Fig. 3). None of the infants we treated had respiratory tract involvement. One infant in our series presented hemangiomatosis, although no visceral organs were affected. We decided to start treatment when we saw that the number of lesions had reached 23, after increasing by 2 every day. With treatment, no new hemangiomas presented and the already evident lesions decreased in number. In a previously reported case, diffuse neonatal hemangiomatosis associated with lesions on visceral organs responded to propranolol.28

We observed the rapid resolution of ulceration in all cases where that complication was present, regardless of whether the hemangioma was on the lip (Fig. 4), elsewhere on the face, or on the back or arm. Oral corticosteroids had been given to all the infants with ulcerated hemangiomas. As those drugs were quickly withdrawn so that propranolol therapy could begin, we conclude that corticosteroid treatment did not have a decisive effect on the final result obtained. The time until appearance of scarring, which would indicate the moment of peak effect, ranged from 2 to 6 months (mean, 4.2 months). Some authors who have reported excellent results recommend that propranolol be considered a first-line option for ulcerated infantile hemangiomas.9 However, others have observed inadequate resolution of ulceration with propranolol treatment in most cases,3 so the suggestion that this drug is a clear alternative to corticosteroids or laser therapy29 remains to be demonstrated.

We would like to emphasize how quickly improvement could be seen in a high percentage of cases. Some parents reported changes (fading of color or softening of the lesion) only 2 days after treatment began, and we observed such changes at the 5-day check-up. When the eye was occluded, opening was achieved within a week of treatment (Fig. 1). The peak effect most often occurred before 5 months of therapy in our series, and in only 3 cases did the first sign of response come late (at 1 month). These observations are consistent with the literature regarding rapid onset of effect3,11,12 and time required to reach the peak response.14 When onset of effect came early in our patients, the overall outcome was good or excellent. When response came later, however, the overall effect was less complete. Such cases might be considered partial responses and possibly dosage increases should be considered early.

Most infants in our series were treated for 6 to 7 months; 1 infant was treated for 14 months and 3 were still on treatment when the study ended. The endpoint of treatment is an important issue because propranolol is known to have an effect not only in the proliferative phase but also later and it is not clear when treatment should cease.30 Following practices that tend to be accepted at present, we continued treatment for 6 months or until the end of the proliferative phase to guard against regrowth. In 2 cases (patient numbers 1 and 10), regrowth occurred when the dosage was lowered and in 1 case (number 8) regrowth started after withdrawal of the drug altogether. Treatment had to be reinstated in those cases. Propranolol also acts after the proliferative phase and if treatment must be restarted it has been seen to act with the same efficacy.4

Most side effects of treatment in our patients were nonspecific and of little clinical significance, although events described in the literature have included sleep disturbances, listlessness, restlessness, loss of appetite, or cold fingers and toes. We did not observe any of the more serious adverse effects, such as hypoglycemia, hypotension, diarrhea, hypokalemia, or respiratory difficulty. The episode of bronchiolitis in our series did not prevent the infant from continuing propranolol treatment once the infection had been brought under control.

Propranolol treatment arrests the progression of growth in the proliferative phase and accelerates the involution phase but does not achieve complete disappearance of the hemangioma in most cases. However, therapy does lead to significant improvement, in the form of reduced volume and clearing or fading of color. Residual effects, such as pigmentation changes, telangiectasia, or scarring are seen even in cases in which response has been classified as excellent. The presence of hemosiderotic coloring at the edges of a lesion may be transient, attributable to blood deposited as vessels are destroyed. Once the peak effect has been reached, further improvement is unlikely to derive from indefinitely prolonging treatment of the hemangioma.

In conclusion, even considering the limitations of this small case series, we feel that propranolol is an effective, fast-acting drug for treating infantile hemangioma. However, as therapy does not achieve complete resolution, pigmentation changes, telangiectasia, or superficial scarring will remain. We also conclude that this use of propranolol is safe, does not cause significant side effects, and can be monitored on an outpatient basis.

The authors declare that they have no conflicts of interest.