To report the long-term results of treatment of pediatric capillary hemangiomas with oral propranolol.
Three infants, 3 to 4 months of age, with periocular capillary hemangiomas were treated with oral propranolol solution (Inderal, 20mg/5ml) 2-3 mg/kg per day divided in 2 doses. Propranolol was continued up to the end of the first year of life and tapered over 2-3 weeks. All infants were followed for 20 months. Lesion size and evolution were assessed during the follow-up period.
Significant improvement was noted in all patients in the first 2 months of therapy with slow and continuous effect throughout the follow-up period. No serious complications were observed.
Oral propranolol can be used as a first line agent in children with capillary hemangiomas.
Oral Propranolol; Capillary Hemangioma
Question I see many children with infantile hemangiomas and have read about new therapeutic options such as propranolol. Is this medication effective and safe for treating hemangiomas in children?
Answer Most infantile hemangiomas resolve spontaneously without any need for therapy. In many case series, propranolol has been shown to be effective and safe in treating hemangiomas that cause complications. Further studies are required to determine the optimal dose and duration of propranolol treatment for problematic hemangiomas.
To investigate the efficacy and safety of oral propranolol in the management of periorbital infantile hemangioma in four subjects.
Materials and Methods:
Consecutive patients who presented with periorbital capillary hemangioma with vision-threatening lesions were prospectively enrolled in this study between January 2009 and October 2010. All subjects underwent treatment with 2 mg/kg/day oral propranolol. All subjects underwent ocular, systemic, and radiologic evaluations before treatment and at periodic intervals after starting therapy. Side effects from therapy were also evaluated.
Four subjects, between 3 months and 19 months of age, with periorbital hemangioma were enrolled in this study. Two subjects had been previously treated with oral corticosteroids with unsatisfactory response. All subjects had severe ptosis, with the potential for deprivation amblyopia. Three subjects had orbital involvement. After hospital admission, oral propranolol was initiated in all subjects under monitoring by a pediatric cardiologist. Subsequent therapy was performed with periodic out-patient monitoring. All subjects had excellent response to treatment, with regression of periorbital and orbital hemangioma. There were no side effects from therapy.
Oral propranolol for periorbital hemangioma was effective in all the four subjects. Oral propranolol may be appropriate for patients who are nonresponsive to intralesional or systemic steroids. In patients with significant orbital involvement and lesions causing vision-threatening complications, oral propranolol can be the primary therapy.
Amblyopia; Infants; Orbital Hemangioma; Propranolol
Oral propranolol has become a promising treatment of capillary hemangiomas (CHs) despite concerns of side effects associated with systemic beta-blockers. The objective of this study was to investigate the distribution of propranolol in periocular tissues and in plasma after topical application of propranolol as compared with intravenous and oral administration of propranolol.
Each rabbit received propranolol as ophthalmic solution (1%) in one eye (1.5 mg dose), intravenous injection (1.5 mg dose), or commercially available propranolol oral solution (5 mg dose). The periocular tissues (e.g., eyelids and extraocular muscles) and blood were collected and assayed for propranolol.
After topical instillation of 1.5 mg propranolol, high amounts of propranolol were rapidly delivered to the eyelids and extraocular muscles (4−32 μg/g at 1 h after dosing). The drug in these tissues was slowly cleared, and significant amounts of the drug (>0.4 μg/g) were still present at 24 h after the topical application. After oral administration of a clinically relevant dose of 5 mg propranolol, the drug concentrations in the periocular tissues were relatively low (<0.4 μg/g) at 1 h after dosing and generally undetectable at 8 h after dosing. After an intravenous injection of 1.5 mg propranolol, the drug concentrations in the eyelids and extraocular muscles were in the range of 0.2−1 μg/g at 1 h after dosing. The plasma concentration of the drug after the intravenous injection was significantly higher than that after topical application of the same dose. The higher drug concentrations in the periocular tissues of the treated eyes as compared with untreated eyes suggest direct penetration of the drug into the periocular tissues from the administration site after topical application.
Topical administration can provide increased concentrations of propranolol in the periocular tissues and, thus, is superior to systemic administration for the treatment of periocular CH.
Propranolol has emerged as a new treatment option for infantile hemangiomas. We describe a 20-month-old boy with a large right parotid hemangioma diagnosed at the age of 37 days. Starting at the age of 2.5 months, he received oral propranolol for 6.5 months. Although the mass regressed, it recurred when propranolol was discontinued. He was successfully retreated at the age of 11 months with propranolol for another 5.5 months without further recurrences. Treatment was tolerated well. Our paper and a review of the literature demonstrate that propranolol appears to be safe and effective for symptomatic infantile parotid gland hemangiomas.
When used in the treatment of hypertension propranolol is at least of similar potency to bethanidine, guanethidine, and methyldopa. Propranolol does not produce postural or exercise hypotension and it seems that it is often more acceptable to patients than conventional drugs. It usually produces the best control of the supine blood pressure.
A series of 109 hypertensive patients was treated with propranolol; in nine the drug was withdrawn. In 92 of the patients a supine or standing blood pressure of 100 mm. Hg or less was achieved. Eighty of the patients had previously been treated with other potent drugs, and close comparisons and prolonged follow-up in 17 patients showed that diastolic pressures of 100 mm. Hg or less were achieved in more patients after propranolol than with guanethidine, bethanidine, or methyldopa.
Sensitivity to propranolol varies widely, and dosage should be increased gradually. The hypotensive effect often takes six to eight weeks to reach its maximum. Propranolol reduces cardiac output but may also act by reducing the cardiac component of pressor stimuli; as a result the baroreceptors gradually regulate the blood pressure at a lower level. It is contraindicated in patients with obstructive airways disease or in uncompensated heart failure.
We hypothesized that some characteristics of beta-blockers, including negative inotropic, peripheral vasoconstrictor, and antiangiogenic effects, might be potentially useful in treating children with epistaxis. From June 2010 to March 2012, a total of seven children with recurrent primary epistaxis resistant to conventional management were observed at our institution. An overall effectiveness of propranolol was noted in all seven children when given a dose of 1.5–2 mg/kg/day (divided into three doses) as a second line therapy for terminating epistaxis. Based on our first experience, we believe that propranolol could be a favorable treatment option for patients with primary epistaxis.
beta-blocker; epistaxis; children
Infantile hemangioma (IH) is a common childhood vascular tumor. Although benign, some hemangiomas cause deformation and destruction of features or endanger life. The current treatments, corticosteroid or propranolol, are administered for several months and can have adverse effects for the infant. We designed a high-throughput screen to identify FDA-approved drugs that could be used to treat this tumor. Rapamycin, an mTOR inhibitor, was identified based on its ability to inhibit proliferation of a hemangioma-derived stem cell population, human vasculogenic cells we had previously discovered. In vitro and in vivo studies show that Rapamycin reduces the self-renewal capacity of the hemangioma stem cells, diminishes differentiation potential, and inhibits the vasculogenic activity of these cells in vivo. Longitudinal in vivo imaging of blood flow through vessels formed with hemangioma stem cells shows that Rapamycin also leads to regression of hemangioma blood vessels, consistent with its known anti-angiogenic activity. Finally, we demonstrate that Rapamycin-induced loss of stemness can work in concert with corticosteroid, the current standard therapy for problematic hemangioma, to block hemangioma formation in vivo. Our studies reveal that Rapamycin targets the self-renewal and vascular differentiation potential in patient-derived hemangioma stem cells and suggests a novel therapeutic strategy to prevent formation of this disfiguring and endangering childhood tumor.
To determine the effectiveness and possible side effects of using propranolol for the treatment of orbital and periorbital infantile hemangiomas.
Infants with periorbital or orbital hemangiomas who had not received either local or systemic corticosteroids were recruited. The changes in tumor size, color, and texture, and any side effects of the drug were recorded.
Fifteen infants with a mean age of 8.13 ± 4.7 months were treated according to the set protocol. A change in the color and texture of the hemangioma occurred in the first week following treatment. Mean duration of treatment was 7.67 ± 3.96 months. The size of hemangiomas decreased from a mean of 2.4 ± 0.9 cm to a mean of 1.6 ± 1.0 cm 3 months after treatment (P = 0.001). One patient had to stop the drug because of peripheral vascular ischemia. Another case had the dose reduced to control a mild hyperglycemia. Serious side effects were not observed. A single case of tumor regrowth (8.3%) was recorded.
Treatment of 1–2 mg/kg/day propranolol proved to be effective and associated with minimal side effects. It is likely to replace steroids as the first-line of treatment of hemangiomas in infants.
orbital and periorbital hemangioma; β-blockers; propranolol; corticosteroids; adrenal suppression
In a crossover study 32 patients with hypertension were randomly allocated to treatment with spironolactone 200 mg/day for two months, propranolol 320 mg/day for two months, and a combination of both drugs at half the dose. Between the treatments placebo was given for two months. Both spironolactone and propranolol lowered the blood pressure significantly in both positions. The initial plasma renin activity (PRA) levels ranged from 0-4 to 5-0 mug angiotensin I l-1 h-1, and there was a close correlation between these levels and the effects of the drugs: with increasing PRA the response to propranolol was better while the opposite was true for spironolactone. Spironolactone reduced the blood pressure more at eight than at four weeks, while no such difference could be shown for propranolol. Spironolactone and propranolol together decreased the blood pressure still further irrespective of the initial PRA. All patients achieved a normal supine blood pressure.
Several therapeutic approaches have been developed to treat choroidal hemangioma. However, all these therapies are associated with a potential risk of damaging the overlying retina.
We report a case of circumscribed choroidal hemangioma (CCH) in a 59-year-old man refractory to laser treatment. Visual acuity was 20/200 and a serous macular detachment was present. The CCH was treated with oral propanolol, whereupon visual acuity improved to 20/20 and the macular detachment resolved without systemic or local adverse effects.
Propanolol is a β-blocker commonly used in cardiology that may induce endothelium vasoconstriction and inhibit endothelial proliferation. It has been shown to be effective in infantile facial hemangiomas, and proved safe and effective for the CCH in our patient. Further studies are needed to confirm our observation.
Circumscribed choroidal hemangioma; Propanolol; β-Blocker
The purpose of this study was to evaluate the use of intralesional propranolol injection in the management of periocular capillary hemangioma.
A prospective study was performed in 22 consecutive patients with periocular hemangioma. Twelve patients underwent intralesional propranolol injection and ten patients underwent intralesional triamcinolone injection. The size of the lesion was measured serially every week during the first month, every 2 weeks for the second month, and then monthly for another 2 months. The refractive error and degree of ptosis if present were measured before injection and at the end of the study.
There was reduction in the size of hemangioma, astigmatic error, and degree of ptosis in both groups. The difference in outcome between both groups was not statistically significant. Rebound growth occurred in 25% of the propranolol group and 30% of the steroid group but responded to reinjection. No adverse effects were reported during or after intralesional propranolol injection.
Intralesional propranolol injection is an alternative and effective method for treatment of infantile periocular hemangioma.
propranolol; intralesional; periocular capillary hemangioma
The relationship between plasma propranolol concentration and relief of essential tremor was examined in 11 patients during treatment with oral racemic propranolol in doses of 30 to 640 mg/day. Although propranolol decreased tremor in all 11 patients, the degree of improvement varied widely in individuals (mean 51%, range 25--90%), and was not related directly occurred at plasma propranolol concentrations below 20 ng/ml (0.077 mumol/l) and, in three others, below 40 ng/ml (0.154 mumol/l). It is concluded that the optimum response of essential tremor to propranolol is achieved at relatively low plasma propranolol levels, levels which are obtained by daily propranolol doses of 120--240 mg.
The management of hemangiomas has always been a matter of controversy. Traditionally, observation has been the mainstay of therapy, with the expectation that most of the lesions will disappear spontaneously. This treatment plan was based on the premise that surgical excision or other treatments might produce a worse result than simply waiting for the lesion to resolve with an acceptable cosmetic result. This plan has been challenged because of a growing number of specialty teams that address these lesions. This article examines various cases of pediatric hemangioma and evaluates the possibility of surgical excision as a first-choice treatment in these cases. One hundred fifteen cases of surgical excision of pediatric hemangiomas performed by a single surgeon over a period of 7 years were examined. Pre- and postoperative photographs were examined. Hemangioma location, size, and type; patient's age; and surgical technique are described. Acceptable cosmetic and functional results were achieved in all surgical cases. Early excision of hemangioma should be the procedure of choice in selected cases of hemangioma. Hemangiomas in areas where a significant cosmetic defect or functional defect might ensue should have surgical excision considered as first-line treatment.
Hemangioma; surgical excision; pediatric
We compared the antianginal efficacy of one conventional and three long acting beta-adrenoreceptor blocking agents in a randomised manner in 12 patients with stable angina pectoris. An exercise test was performed initially and in the 24th hour after a single daily dose of 160 mg of each beta-blocker at the end of a two week treatment period. In addition, glyceryl trinitrate consumption, anginal attack rate, and activity scores were recorded. No titration studies to an equivalent degree of beta-blockade were undertaken; a fixed dose was used even though these drugs are not equipotent. Conventional propranolol in a single daily dose of 160 mg was as effective in controlling the frequency of anginal attacks as long acting propranolol and sustained release oxprenolol. Exercise tolerance was less with sustained release oxprenolol than with conventional propranolol, long acting propranolol, and nadolol. Nadolol produced a significantly greater reduction in exercise-induced tachycardia than did long acting propranolol, sustained release oxprenolol, and conventional propranolol, and also the lowest anginal attack rate, the lowest trinitrin consumption, and significantly less ST segment depression than the other three. These findings suggest that nadolol is more potent than long acting propranolol, sustained release oxprenolol, and conventional propranolol, and the antianginal benefit at the 24th hour relates to the degree of beta-adrenoreceptor blockade achieved.
Uptake of 14C-propranolol by the lungs during a single passage through the pulmonary circulation was measured in ten patients at cardiac catheterisation. Mean lung uptake of propranolol was 75% in seven patients who were not previously taking the drug and 33% in three patients who were taking it as regular oral treatment. Lung uptake of propranolol in man is therefore considerable and is partly saturable by normal oral doses. This may alter the dose response relation for propranolol and a wide range of other drugs when given intravenously. The method used to study lung uptake is simple and might be suitable for studies of endothelial cell function in disease.
A trial of oral propranolol as a hypotensive agent was designed to provide adequate treatment periods. Twenty-eight patients with essential hypertension, with a mean blood pressure of 190/111 mm. Hg, were controlled on 120-320 mg. of propranolol daily. Their mean treated blood pressure was 153/91. They then entered, on a randomized and double-blind basis, a cross-over trial of two 16-week periods, blood pressure being measured fortnightly. Propranolol caused a statistically significant fall in blood pressure when compared with placebo. When propranolol was withdrawn blood pressures rapidly rose to hypertensive levels, though not to untreated levels. No postural hypotension was found, but a small change in blood pressure levels on exercise was noted.
Haemangiomas represent the most common benign tumours in infancy, affecting 1-2% of newborns. The present meta-analysis aimed to critically review the current evidence on the efficacy of propranolol in the management of airway haemangiomas, and explore potential adverse events and treatment failures. A literature review was performed in Medline and other available database sources, along with critical analysis of pooled data. Seventeen studies were included in the analysis. No study represented Level I evidence. The total number of treated patients was 61; 14 patients received propranolol as single-treatment. The comparative effectiveness of propranolol vs. systemic steroids was documented in 35 children, and showed superior outcome in the vast majority (94%, p < 0.001). The mean obstruction before propranolol administration was 72%, and after intervention was 20% (p < 0.001). The mean referral-age for children with airway haemangiomas was 2.4 months, the mean starting-age of propranolol treatment was 5.1 months and the mean follow-up period was 8.4 months. Four children failed to respond (6.5%), and in seven the haemangioma relapsed after discontinuation of treatment (11.5%). The results of the present study suggest that propranolol can be recommended for the treatment of airway haemangiomas, as it was found to be effective and outperformed the previously-considered gold standard treatment methods, with fewer side-effects. Immediate treatment with propranolol should be initiated once a diagnosis of symptomatic airway haemangioma is confirmed, and cardiovascular assessment has been performed. Children should remain on propranolol until the haemangioma enters the phase of involution. Active parental monitoring is essential to ensure treatment safety.
Haemangioma; Airway; Propranolol; Steroids
Corticosteroids are commonly used to treat infantile hemangioma, but the mechanism of action of this therapy is unknown. We investigated the effect of corticosteroids in a previously described in vivo model of infantile hemangioma and in cultured hemangioma-derived cells.
We tested hemangioma-derived stem cells for vasculogenic activity in vivo after implantation into immune-deficient (nude) mice. We studied dexamethasone treatment of both the cells before implantation and the mice after implantation. We also tested hemangioma-derived stem cells for expression of vascular endothelial growth factor A (VEGF-A) in vitro and studied the inhibition of VEGF-A expression, using short hairpin RNA (shRNA) in vivo and in vitro.
Systemic treatment with dexamethasone led to dose-dependent inhibition of tumor vasculogenesis in the murine model. Pretreatment of hemangioma-derived stem cells in vitro before implantation also inhibited vasculogenesis. Dexamethasone suppressed VEGF-A production by hemangioma-derived stem cells in vitro but not by hemangioma-derived endothelial cells or human umbilical-vein endothelial cells. Silencing VEGF-A in hemangioma-derived stem cells reduced vasculogenesis in vivo. VEGF-A was detected in hemangioma specimens in the proliferating phase but not in the involuting phase and was shown by immunostaining to reside outside of vessels. Corticosteroid treatment suppressed other proangiogenic factors in hemangioma-derived stem cells, including urokinase plasminogen activator receptor, interleukin-6, monocyte chemoattractant protein 1, and matrix metalloproteinase 1.
In a murine model, dexamethasone inhibited the vasculogenic potential of stem cells derived from human infantile hemangioma. The corticosteroid also inhibited the expression of VEGF-A by hemangioma-derived stem cells, and silencing of VEGF-A expression in these cells inhibited vasculogenesis in vivo.
Targeting of the vascular endothelium compartment explains, in part, the therapeutic efficacy of the nonselective β-adrenergic antagonist propranolol against common endothelial tumors such as hemangiomas. In vitro, the antiangiogenic biological activity of propranolol was shown to inhibit human brain microvascular endothelial cell tubulogenesis. However, possible interference of propranolol with cell signaling associated with the tumoral compartment remains unexplored. We therefore assessed the potency of propranolol against a pediatric brain tumor- derived DAOY medulloblastoma cell model. Gene expression of β1-, β2-, and β3-adrenergic receptors was confirmed in DAOY cells by semiquantitative RT-PCR. We next found that propranolol dose-dependently inhibited induction of the key extracellular matrix-degrading and blood–brain barrier disrupting enzyme matrix metalloproteinase- 9 (MMP-9) by phorbol 12-myristate 13-acetate (PMA). Propranolol not only inhibited PMA- induced phosphorylation of the extracellular signal-regulated kinase (Erk), but also that of IkappaB (IκB), preventing the IκB phosphorylation which is a prerequisite for IκB degradation. Propranolol inhibition of IκB phosphorylation was shown to occur with optimal efficacy at 30 μM. Although propranolol, at up to 100 μM, did not affect cell viability, it potentiated PMA- mediated signaling that ultimately led to diminished phosphorylation of Akt. The anti-Erk and anti-Akt phosphorylation effects are both suggestive of antiproliferative and antisurvival signaling, respectively. Our data are therefore indicative of a pharmacological role for propranolol against β-adrenergic receptor signaling functions involving the nuclear factor-kappaB-mediated regulation of MMP-9.
medulloblastoma; β-adrenergic receptors; MMP-9; NF-κB
Ten men with stable angina pectoris not fully relieved by optimal doses of propranolol (mean 218 mg daily) were given a single oral dose of 120 mg verapamil or a placebo on alternate mornings; the order of treatment was double blind. Patients had trained in a protocol that precipitated angina after three to six minutes of exercise on a bicycle ergometer. On test days, and with continued propranolol treatment, bicycle exercise was performed just before the administration of verapamil or placebo and hourly thereafter for eight hours. Mean exercise tolerance was 118 seconds greater one hour after verapamil than one hour after placebo (p <0·001), and a significant though somewhat diminished difference of 66 seconds was still present at six hours (p <0·01). Verapamil lowered resting systolic blood pressure by 12 mm Hg (p <0·01) without changing heart rate. None of the 10 patients showed adverse effects from the verapamil-propranolol combination.
The results of this study suggest that verapamil is a highly effective antianginal supplement to propranolol.
When propranolol is given to prevent hypoxaemic episodes in children with tetralogy of Fallot who are awaiting operation it is advisable to continue the treatment until shortly before the induction of anaesthesia. Because catecholamines are often required to maintain adequate cardiac output after surgical correction the effect of preoperative treatment with beta blockers on the response to isoprenaline after the operation was investigated in nine children given propranolol before operation and nine who were not. They were studied three and 24 hours after cardiopulmonary bypass. The haemodynamic response to increasing doses of infused isoprenaline was monitored. Immediately after cardiopulmonary bypass the response to isoprenaline was significantly blunted in the patients who had been given propranolol before operation. Their dose-response curve lay to the right of that for patients not given propranolol, and this indicates competitive inhibition. Propranolol concentrations in the blood and myocardium correlated significantly with the heart rate response to isoprenaline. Twenty four hours after operation the isoprenaline response was similar in both groups and concentrations of propranolol in the blood were minimal or undetectable. beta Blockers given up to the time of operation significantly altered the postoperative response to catecholamines.
Twenty-one patients with muscular subaortic stenosis were treated with oral propranolol for periods of 6 to 34 months for a total of 42.5 patient years. The average follow-up was 2 years. Four patients with latent obstruction became asymptomatic on propranolol therapy. Of the 17 patients with resting obstruction, 7 improved, 2 were unchanged, 5 deteriorated, and 2 died during the period of treatment. The 7 patients with resting obstruction who are still improved on propranolol have had relatively short periods of treatment (average 15 months), and none experienced the degree of improvement that occurred in the patients with latent obstruction. This study indicates that propranolol is most effective in patients with muscular subaortic stenosis who have latent obstruction. It is of limited value in patients with resting obstruction because the benefit of propranolol therapy in the majority of these patients is eventually overtaken by progression in the disease.
Propranolol can prevent variceal bleeding by ameliorating portal hypertension. We conducted this study to determine the effect of propranolol on portal hypertension and the optimal required dose in Korean cirrhotic patients.
This study prospectively evaluated 50 patients with cirrhosis who exhibited variceal bleeding. The hepatic venous pressure gradient (HVPG), portal venous flow, heart rate (HR), and blood pressure were assessed both at baseline and at 3 months after the treatment. The initial dose of propranolol (20 mg) was subsequently adjusted until the target HR was reached. Patients in whom HVPG reduced by >20% or to less than 12 mmHg were defined as responders.
Propranolol significantly (p<0.01) reduced the HVPG (-21±26%, mean±standard deviation), portal venous flow (-25±21%), HR (-20±13%), and blood pressure (-3±13%). Twenty-nine patients were responders, and the optimal required dose was 154.4 mg. The main complication was dizziness (24%), but this was not serious enough to require medication withdrawal.
Propranolol is safe and effective at reducing portal pressure in Korean cirrhotic patients. An effective improvement in portal hypertension requires the dose to be increased until the target HR is reached.
Propranolol; Portal hypertension; Liver cirrhosis; Pressure
The effects of 100 mg indomethacin daily for three weeks on blood pressure and urinary excretion of prostaglandin F2 alpha were studied in a double-blind, placebo-controlled comparison of two groups of patients with essential hypertension, eight receiving propranolol and seven thiazide diuretics. Compared with placebo, adding indomethacin to the patients' established antihypertensive treatment increased blood pressure by 14/5 Hg supine and 16/9 mm Hg erect in the patients receiving propranolol, and by 13/9 mm Hg supine and 16/9 mm Hg erect in the patients receiving thiazide diuretics (all p less than or equal to 0.05). The excretion of the major urinary metabolite of prostaglandin F2 alpha was reduced by 67% in the propranolol-treated patients and by 57% in those receiving a thiazide diuretic. Body weight increased by 0 . 8 kg (propranolol) and 1 . 1 kg (thiazide diuretic) when indomethacin was given, but there were no significant changes in creatinine clearance, urinary sodium excretion, or packed cell volume in either treatment group. These results suggest that products formed by the arachidonic acid cyclo-oxygenase contribute to the regulation of blood pressure during treatment with both propranolol and thiazide diuretics. Inhibition of the cyclo-oxygenase with indomethacin partially antagonises the hypotensive effect of these drugs.