Propranolol in Complicated Infantile Hemangioma
Propranolol in Complicated Infantile Hemangioma
Based on the currently available data, propranolol appears to be more successful for the treatment of IH than any other treatment modality, with a possible exception of surgery in selected cases. It is anticipated that this will be progressively demonstrated in emerging randomized controlled trials, one of which has been published with promising outcomes.
Propranolol is a highly lipophilic nonselective beta-adrenergic antagonist with an inhibitory effect on both β1- and β2-adrenoceptors with similar affinity. Its main effect in IH can be explained by different mechanisms: vasoconstriction; inhibition of angiogenesis by downregulation of angiogenic factors, vascular endothelial growth factor and basic fibroblast growth factor; and induction of apoptosis of capillary endothelial cells. These mechanisms correspond, respectively, with the following clinical observations: softening and fading, cessation of growth, and long-term regression.
As IHs have variable localization, size and type, it is almost impossible to describe the treatment effect in a standardized manner. Therefore, in this study a treatment was considered successful if obvious improvement was seen in colour and size, as evaluated subjectively by two observers. In 173 of the cases (99·4%) propranolol treatment was successful; fading and softening of the IH was seen, usually starting within 72 h after the start of treatment. Growth of the IH stopped in all cases and regression was judged as significant at the end of treatment (9–18 months).
Like many drugs used in children, there are no pharmacokinetic data and no prospective controlled studies that can be used to make an adequate treatment regimen and follow-up scheme for this patient group. At the current time, a target dosage of 2–3 mg kg daily, with regular adaption to the body weight, is considered a safe and effective dosage for the healthy infant. However, in the recent literature a minimal dosage required to induce involution of 1·5–2·0 mg kg daily has been described. This was also the case for several patients in this study. The target dosage could be adjusted downwards successfully during initiation or during the course of the treatment, which appears to indicate that for certain patients lower dosages may also be effective. Large-scale studies are required to establish the optimal dosage. In some cases, especially in patients with IH with airway involvement, higher dosages (3 mg kg daily) and strict dose adjustments were necessary, because the effect of propranolol on stridor diminished at the moment that the relative dose decreased due to the weight gain of the child.
Treatment duration was adjusted for the type of IH and the specific treatment indication. In deep and mixed IHs the proliferation phase starts and stops later, treatment was therefore continued until the age of 12–16 months. In cases of ulceration, for example, treatment was continued to 9–12 months of age, because of the marginal risk of recurrence of ulceration after this phase. Deep periorbital IHs and airway IHs, on the other hand, required treatment up to 15–18 months of age, because of the potential life-threatening implications of swelling after cessation of treatment.
Rebound swelling in this study was generally not interpreted as regrowth but as swelling that occurred due to decreased vasoconstriction after stopping propranolol. This refill seems to occur particularly in more bulky IHs, which exhibit a sponge-like residual lesion.
At the end of the treatment period, a slow reduction of the dose in 2 or 3 weeks is indicated, as abrupt discontinuation of beta-blockers bears the risk of cardiac hyper-reactivity due to upregulation of beta-receptors.
Propranolol has been used for more than 40 years in young children aged < 7 years, particularly for cardiological indications, without severe cardiovascular events or lethal outcome. Adrenergic beta-antagonists have a well-documented safety and side-effect profile. The main side-effects of propranolol are bradycardia, hypotension and hypoglycaemia. In addition, bronchospasm, rash, gastrointestinal symptoms, fatigue, behavioural changes, peripheral vasoconstriction and sleep disturbances have also been described. The most serious side-effect of propranolol is hypoglycaemia, also reported following its use for IHs, either aggravated or not by the fact that propranolol can mask early clinical symptoms of hypoglycaemia. The patient groups with higher risks for hypoglycaemia are patients aged < 3 months with decreased food intake or concomitant treatment with oral corticosteroids, in particular in a reduction schedule. In these patient categories, intensive and frequent monitoring is therefore recommended as well as good instructions for parents. In our patient group, the measured fasting glucose levels were normal and fortunately no hypoglycaemic side-effects were seen.
Additionally, propranolol diminishes cardiac performance and can mask the clinical signs of cardiac failure. This means that special care must be taken in patients with cardiac comorbidity, particularly in patients with cardiac failure, due to a large, bulky IH.
With our increasing experience with propranolol, in selected cases we chose to start the lowest dose at home and to increase to the target dosage during day care. This protocol was followed in patients born at term, with normal birthweight and no abnormalities on physical examination or ECG. In all other cases, treatment was started in hospital. Complication rates were similar for in- and outpatients. Important advantages of the outpatient start are the quick and easy application of the treatment without any time delay due to limited clinical capacity, and the fact that it is more cost-effective and patient friendly. The main disadvantage of outpatient initiation of propranolol treatment is the absence of monitoring of blood pressure and heart rate during the first doses. This is why this protocol was applied only to a minority of children; initiation of propranolol in a clinical setting is still our preference.
Following the observation of Léauté-Labrèze et al., several case series have been described in which a large variety of clinically different IHs were treated successfully with propranolol. Initially, predominantly complicated IHs were treated. The indications are gradually broadening and are starting to include cosmetically disturbing cases such as large facial IHs.
For both indications (functional and cosmetic), early initiation of treatment is probably the best, before rapid expansion of the tumour. If the IH is located mainly in important cosmetic areas, an early start with propranolol treatment may reduce the residual lesions after involution, making cosmetic correction less complicated or even unnecessary. To date, there is no evidence that early propranolol treatment leads to less disturbing residual lesions. However, for ulcerated IHs an early start appeared to result in shorter ulceration time; an analogy with less severe residual lesions due to an early start seems likely. Future research will determine the appropriate cosmetic indications. This shift in indications makes timely assessment by an experienced physician necessary.
In accordance with recent literature, we also noted a positive effect on the rate of involution in the few cases where propranolol was started at the end of the growth phase or thereafter. However, the residual lesions (e.g. fibro-fatty tissue, skin surplus) are expected to be comparable with the situation in which treatment was not administered.
Besides treatment modifications pertaining to initiation and/or duration, future developments may include the use of more selective beta-blockers. Reports on selective beta-blockers, such as atenolol or acebutolol, have already been published, but further investigation is required as to whether this selectivity is accompanied by a more favourable safety–efficacy profile.
Alternative approaches, such as the possible beneficial effect of angiotensin-converting enzyme (ACE) inhibitors, will be further explored in the future. The renin–angiotensin system has recently been determined as a factor in the pathogenesis of IH. Expression of ACE and angiotensin II receptor-2 on immature capillaries of a proliferating IH has been observed and it has been proposed that beta-blockers decrease renin activity, resulting in decreased angiotensin II in IH tissue, leading to accelerated involution. The ACE inhibitor captopril was recently reported to be effective.
There is currently limited experience with the application of topical beta-blockers such as timolol. A beneficial effect can be seen, especially in superficial IHs, but the topical approach seems insufficient for the expansive growth of bulky deep IHs. On the other hand, application of topical beta-blockers in very young children (aged < 4 weeks) with a still flat IH appears to be a therapeutic option. However, topical beta-blockers must be prescribed with caution, especially in larger lesions, because of the risk of systemic absorption and subsequent side-effects.
In conclusion, propranolol is definitively a valuable and promising therapeutic option for IH. In our patient group it was effective and safe in almost all patients. However, for some patients dose adjustments were necessary because of side-effects. Future research is required on the treatment regimen and long-term follow-up. From the extensive experience of our tertiary referral centre and data from the literature, we expect that in the near future propranolol will become the first-choice treatment in complicated and disfiguring IHs, and very likely with further expanding areas of indication.
On the other hand, it is important to emphasize that giving beta-blockers to young infants has to be justified for each individual patient as IHs are common, benign, self-limiting tumours that usually do not need an active approach. Only a small minority of IHs are life or function threatening, and require therapy. Large, facial IHs with serious cosmetic outcomes may also be eligible for an active approach. Therefore, patients with life-threatening lesions or lesions with a severe psychosocial impact should be assessed individually and early by an experienced physician or a dedicated multidisciplinary team. The characteristics of the IH and the patient and the potential risk of propranolol treatment need to be taken into account.
Discussion
Based on the currently available data, propranolol appears to be more successful for the treatment of IH than any other treatment modality, with a possible exception of surgery in selected cases. It is anticipated that this will be progressively demonstrated in emerging randomized controlled trials, one of which has been published with promising outcomes.
Propranolol is a highly lipophilic nonselective beta-adrenergic antagonist with an inhibitory effect on both β1- and β2-adrenoceptors with similar affinity. Its main effect in IH can be explained by different mechanisms: vasoconstriction; inhibition of angiogenesis by downregulation of angiogenic factors, vascular endothelial growth factor and basic fibroblast growth factor; and induction of apoptosis of capillary endothelial cells. These mechanisms correspond, respectively, with the following clinical observations: softening and fading, cessation of growth, and long-term regression.
As IHs have variable localization, size and type, it is almost impossible to describe the treatment effect in a standardized manner. Therefore, in this study a treatment was considered successful if obvious improvement was seen in colour and size, as evaluated subjectively by two observers. In 173 of the cases (99·4%) propranolol treatment was successful; fading and softening of the IH was seen, usually starting within 72 h after the start of treatment. Growth of the IH stopped in all cases and regression was judged as significant at the end of treatment (9–18 months).
Like many drugs used in children, there are no pharmacokinetic data and no prospective controlled studies that can be used to make an adequate treatment regimen and follow-up scheme for this patient group. At the current time, a target dosage of 2–3 mg kg daily, with regular adaption to the body weight, is considered a safe and effective dosage for the healthy infant. However, in the recent literature a minimal dosage required to induce involution of 1·5–2·0 mg kg daily has been described. This was also the case for several patients in this study. The target dosage could be adjusted downwards successfully during initiation or during the course of the treatment, which appears to indicate that for certain patients lower dosages may also be effective. Large-scale studies are required to establish the optimal dosage. In some cases, especially in patients with IH with airway involvement, higher dosages (3 mg kg daily) and strict dose adjustments were necessary, because the effect of propranolol on stridor diminished at the moment that the relative dose decreased due to the weight gain of the child.
Treatment duration was adjusted for the type of IH and the specific treatment indication. In deep and mixed IHs the proliferation phase starts and stops later, treatment was therefore continued until the age of 12–16 months. In cases of ulceration, for example, treatment was continued to 9–12 months of age, because of the marginal risk of recurrence of ulceration after this phase. Deep periorbital IHs and airway IHs, on the other hand, required treatment up to 15–18 months of age, because of the potential life-threatening implications of swelling after cessation of treatment.
Rebound swelling in this study was generally not interpreted as regrowth but as swelling that occurred due to decreased vasoconstriction after stopping propranolol. This refill seems to occur particularly in more bulky IHs, which exhibit a sponge-like residual lesion.
At the end of the treatment period, a slow reduction of the dose in 2 or 3 weeks is indicated, as abrupt discontinuation of beta-blockers bears the risk of cardiac hyper-reactivity due to upregulation of beta-receptors.
Propranolol has been used for more than 40 years in young children aged < 7 years, particularly for cardiological indications, without severe cardiovascular events or lethal outcome. Adrenergic beta-antagonists have a well-documented safety and side-effect profile. The main side-effects of propranolol are bradycardia, hypotension and hypoglycaemia. In addition, bronchospasm, rash, gastrointestinal symptoms, fatigue, behavioural changes, peripheral vasoconstriction and sleep disturbances have also been described. The most serious side-effect of propranolol is hypoglycaemia, also reported following its use for IHs, either aggravated or not by the fact that propranolol can mask early clinical symptoms of hypoglycaemia. The patient groups with higher risks for hypoglycaemia are patients aged < 3 months with decreased food intake or concomitant treatment with oral corticosteroids, in particular in a reduction schedule. In these patient categories, intensive and frequent monitoring is therefore recommended as well as good instructions for parents. In our patient group, the measured fasting glucose levels were normal and fortunately no hypoglycaemic side-effects were seen.
Additionally, propranolol diminishes cardiac performance and can mask the clinical signs of cardiac failure. This means that special care must be taken in patients with cardiac comorbidity, particularly in patients with cardiac failure, due to a large, bulky IH.
With our increasing experience with propranolol, in selected cases we chose to start the lowest dose at home and to increase to the target dosage during day care. This protocol was followed in patients born at term, with normal birthweight and no abnormalities on physical examination or ECG. In all other cases, treatment was started in hospital. Complication rates were similar for in- and outpatients. Important advantages of the outpatient start are the quick and easy application of the treatment without any time delay due to limited clinical capacity, and the fact that it is more cost-effective and patient friendly. The main disadvantage of outpatient initiation of propranolol treatment is the absence of monitoring of blood pressure and heart rate during the first doses. This is why this protocol was applied only to a minority of children; initiation of propranolol in a clinical setting is still our preference.
Following the observation of Léauté-Labrèze et al., several case series have been described in which a large variety of clinically different IHs were treated successfully with propranolol. Initially, predominantly complicated IHs were treated. The indications are gradually broadening and are starting to include cosmetically disturbing cases such as large facial IHs.
For both indications (functional and cosmetic), early initiation of treatment is probably the best, before rapid expansion of the tumour. If the IH is located mainly in important cosmetic areas, an early start with propranolol treatment may reduce the residual lesions after involution, making cosmetic correction less complicated or even unnecessary. To date, there is no evidence that early propranolol treatment leads to less disturbing residual lesions. However, for ulcerated IHs an early start appeared to result in shorter ulceration time; an analogy with less severe residual lesions due to an early start seems likely. Future research will determine the appropriate cosmetic indications. This shift in indications makes timely assessment by an experienced physician necessary.
In accordance with recent literature, we also noted a positive effect on the rate of involution in the few cases where propranolol was started at the end of the growth phase or thereafter. However, the residual lesions (e.g. fibro-fatty tissue, skin surplus) are expected to be comparable with the situation in which treatment was not administered.
Besides treatment modifications pertaining to initiation and/or duration, future developments may include the use of more selective beta-blockers. Reports on selective beta-blockers, such as atenolol or acebutolol, have already been published, but further investigation is required as to whether this selectivity is accompanied by a more favourable safety–efficacy profile.
Alternative approaches, such as the possible beneficial effect of angiotensin-converting enzyme (ACE) inhibitors, will be further explored in the future. The renin–angiotensin system has recently been determined as a factor in the pathogenesis of IH. Expression of ACE and angiotensin II receptor-2 on immature capillaries of a proliferating IH has been observed and it has been proposed that beta-blockers decrease renin activity, resulting in decreased angiotensin II in IH tissue, leading to accelerated involution. The ACE inhibitor captopril was recently reported to be effective.
There is currently limited experience with the application of topical beta-blockers such as timolol. A beneficial effect can be seen, especially in superficial IHs, but the topical approach seems insufficient for the expansive growth of bulky deep IHs. On the other hand, application of topical beta-blockers in very young children (aged < 4 weeks) with a still flat IH appears to be a therapeutic option. However, topical beta-blockers must be prescribed with caution, especially in larger lesions, because of the risk of systemic absorption and subsequent side-effects.
In conclusion, propranolol is definitively a valuable and promising therapeutic option for IH. In our patient group it was effective and safe in almost all patients. However, for some patients dose adjustments were necessary because of side-effects. Future research is required on the treatment regimen and long-term follow-up. From the extensive experience of our tertiary referral centre and data from the literature, we expect that in the near future propranolol will become the first-choice treatment in complicated and disfiguring IHs, and very likely with further expanding areas of indication.
On the other hand, it is important to emphasize that giving beta-blockers to young infants has to be justified for each individual patient as IHs are common, benign, self-limiting tumours that usually do not need an active approach. Only a small minority of IHs are life or function threatening, and require therapy. Large, facial IHs with serious cosmetic outcomes may also be eligible for an active approach. Therefore, patients with life-threatening lesions or lesions with a severe psychosocial impact should be assessed individually and early by an experienced physician or a dedicated multidisciplinary team. The characteristics of the IH and the patient and the potential risk of propranolol treatment need to be taken into account.
