Lymphangioma and Infantile Hemangioma

Number: 0817

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses lymphangioma and infantile hemangioma.

1. Medical Necessity

   Aetna considers the following interventions medically necessary for the managment of lymphangioma or infantile hemangioma when criteria is met:

   1. Treatment for hemangiomas of infancy when:

      1. The lesion:

         1. Compromises vital structures (e.g., nose, eyes, ears, lips or larynx); or
         2. Is associated with Kasabach-Merritt Syndrome; or
         3. Is symptomatic (e.g., bleeding, painful, ulcerated, prior infection, or pedunculated and symptomatic); or
         4. Results in a documented functional impairment; and

      2. Any of the following treatments are used alone or in combination:

         1. Cryosurgery / cryotherapy
         2. Embolization
         3. Intralesional steroids
         4. Laser therapy
         5. Radiotherapy
         6. Sclerosing therapy
         7. Surgical excision;

   2. Oral propranolol for proliferating infantile hemangioma requiring systemic therapy (corticosteroids);

      Note: A hospital stay may be medically necessary to monitor infants' blood pressure, glycemic control and heart rate for possible unwanted reactions (e.g., bradycardia, hypoglycemia and hypotension).

      Inpatient initiation of propranolol is considered medically necessary for infants who:

      1. Are less than or equal to 8 weeks (corrected ageFootnote1*); or
      2. Lack adequate social support; or
      3. Have co-morbid conditions affecting the cardiovascular system, the airway system (including symptomatic respiratory hemangiomas), or blood glucose maintenance.

      Inpatient admission is considered medically necessary until the target does of propanolol is tolerated for 2 hours.  For inpatients, it is suggested that propranolol be initiated at 0.33 mg/kg orally 3 times daily (TID); and BP and HR are checked 1 and 2 hours after each administration.  If 3 doses are tolerated, propranolol is increased to the target of 0.66 mg/kg TID (2 mg/kg/day) with similar BP and HR monitoring.  Once the target dose is tolerated for at least 2 hours, the patient may be discharged.  If dose initiation or escalation is not tolerated, it is recommended the dosage be reduced and then gradually increased until tolerated.

      Footnote1* Corrected age and chronological age are not synonymous in preterm infants."Corrected age" (or "adjusted age") represents the age of the child from the expected date of delivery. Corrected age is calculated by subtracting the number of weeks born before 40 weeks of gestation from the chronological age (AAP, 2004). 

   3. Use of sclerotherapy for treatment of lymphangioma.

2. Experimental and Investigational

   Aetna considers the following interventions / testing / procedures experimental and investigational because the effectiveness of these approaches has not been established (not an all-inclusive list):

   1. Any of the following interventions for treatment of infantile hemangioma:

      1. Atenolol
      2. Pigment epithelium-derived factor (PEDF)
      3. Topical timolol;
   2. Measurements of endothelial and circulating C19MC microRNAs, and serum vascular endothelial growth factor (VEGF) as biomarkers of infantile hemangioma;
   3. Sirolimus for treatment of diffuse intestinal infantile hemangioma.

3. Related Policies

   • CPB 0031 - Cosmetic Surgery - for medically necessary indications for removal of hemangiomas (port wine stains) located on the face and neck

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
There are no specific codes for oral propranolol, atenolol and topical timolol:
CPT codes covered if selection criteria are met:
11400 - 11446	Excision, benign lesions including margins, except skin tag (unless listed elsewhere)
17106 - 17108	Destruction of cutaneous vascular proliferative lesions (eg, laser technique)
17110 - 17111	Destruction (eg, laser surgery, electrosurgery, cryosurgery, chemosurgery, surgical curettement), of benign lesions other than skin tags or cutaneous vascular proliferative lesions
11900 - 11901	Injection, intralesional
77401	Radiation treatment delivery, superficial and/or ortho voltage, per day
CPT codes not covered for indications listed in the CPB:
Measurements of endothelial and circulating C19MC microRNAs, Serum vascular endothelial growth factor (VEGF) – no specific code
Other CPT codes related to the CPB:
77402	Radiation treatment delivery,=>1 MeV; simple
HCPCS codes not covered for indications listed in the CPB:
J7520	Sirolimus, oral, 1 mg
J9331	Injection, sirolimus protein-bound particles, 1 mg
ICD-10 codes covered if selection criteria are met:
D18.00 - D18.09	Hemangioma(s)
D18.1	Lymphangioma, any site
Q82.5	Congenital non-neoplastic nevus

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Background

Nguyen and Fay (2009) noted that infantile hemangiomas are common vascular tumors of childhood with a propensity for the head and neck.  In the peri-ocular region, they can cause functional and cosmetic deformity.  The proliferation and involution of hemangiomas are controlled by complex interactions of molecular, cellular, and hormonal regulators.  There is no single uniformly safe and effective treatment option.  Various modalities, including local and systemic pharmacologic agents, lasers, surgery and embolization, are employed to halt growth and to induce regression.

Buckmiller (2009) stated that infantile hemangiomas are the most common benign tumors of infancy and the majority of them occur in the head and neck.  Recent literature has described propranolol for the treatment of these vascular tumors.  Propranolol was serendipitously found to induce early involution in hemangiomas even during the proliferative phase of the hemangioma cycle.  First reported in June 2008, and presented at the International Society for the Study of Vascular Anomalies meeting in Boston that same month, propranolol has stirred much interest in the physicians who treat these types of lesions.  Early case report data are now appearing in the literature, and are verifying the findings of the initial studies as an effective treatment for hemangiomas.  The author's institution has the privilege of maintaining a high volume vascular center and has begun treating patients with problematic hemangiomas with propranolol as well.  The present article reviewed the literature and give some of our preliminary experience with the drug.  The author concluded that research regarding propranolol is in its infancy but, should the initial results and safety record be borne out, it is likely to revolutionize how infantile hemangiomas is managed.

Leaute-Labreze and colleagues (2008) published a case series in the New England Journal of Medicine, which observed that propranolol could inhibit the growth of infantile capillary hemangiomas.  In several of the 11 cases, the infants were administered corticosteroids, with no improvement.

Maturo and Hartnick (2010) described the initial use of propranolol as the sole treatment for focal infantile airway hemangiomas, and reported on available literature describing the use of propranolol for airway lesions.  This retrospective case series was carried out at a tertiary pediatric medical center.  These researchers obtained the following results: 2 children demonstrated significant response to oral propranolol therapy and avoided not only invasive surgical procedures, but also long-term administration of oral corticosteroids.  This was the first report of treating infantile airway hemangiomas with only propranolol without additional surgical intervention or corticosteroid use.  Review of literature reveals initial case series with similar, successful results using propranolol as an adjuvant treatment along with other medications and surgical interventions.  The authors concluded that the initial use of propranolol as the sole treatment for infantile airway hemangioma is promising.  Literature review reveals that propranolol as the sole treatment for most head and neck hemangiomas shows significant promise based on early case reports.  They stated that further studies are needed to determine the long-term effectiveness, dosing strategies, and side effect profile of propranolol treatment for hemangiomas.

Buckmiller et al (2010) explored the impact of propranolol on both proliferative and involuting hemangiomas at a tertiary vascular anomalies center.  These investigators reviewed children treated with propranolol for problematic hemangiomas followed by a blinded prospective analysis of serial photographs taken during the course of their therapy.  Parental questionnaires were obtained to evaluate perceived therapeutic response and complications to oral propranolol.  A total of 32 children with complete photo documentation were treated with oral propranolol for infantile hemangiomas between September 2008 and June 2009 were included in this analysis.  Twenty-seven patients began therapy during the proliferative phase of their lesions (mean age of 4.9 months), whereas five patients began during the involutional phase (mean age of 19.4 months).  Ninety-seven percent of patients displayed improvement in the quality of their hemangiomas during propranolol therapy.  Patients were determined to be excellent responders (n = 16, 50 %), partial responders (n = 15, 47 %), or non-responders (n = 1, 3 %).  Partial and non-responders received adjuvant therapy (75 %, laser therapy; 31 %, steroid injections).  Ten patients experienced minor but reportable side effects to propranolol, including somnolence (27.2 %), gastroesophageal reflux (9.1 %), respiratory syncytial virus exacerbation (4.5 %), and rash (4.5 %).  The authors concluded that propranolol may revolutionize the treatment of problematic hemangiomas that cause imminent functional or cosmetic sequelae.  At therapeutic doses, propranolol is safe and effective in the majority of patients.  Adjunctive therapies may still be required.  Minor side effects, expected from beta-blocker therapy, are common but easily managed.

Leboulanger et al (2010) provided preliminary assessment of the efficacy of propranolol on subglottic hemangioma in children on a nation-wide scale (multi-centric, retrospective study of clinical files of 14 children; pre- and post-treatment endoscopies).  Mean age at diagnosis was 2.3 (0.7 to 4) months.  Mean percentage of airway obstruction was 68 % (15 to 90) before propranolol introduction.  Propranolol was started at 5.2 (0.7 to 16) months of age.  This treatment was effective in all cases with a mean regression of the stenosis to 22 % after 2 weeks and 12 % after 4 weeks.  Other medical treatments (steroids) could be stopped.  In 1 patient, a side effect of propranolol motivated the switch to another β-blocker.  In 4 patients, treatment was stopped after 5.2 (1 to 10) months with a relapse in 2 (50 %) cases.  One of these 2 patients developed a resistance to propranolol and required a surgical procedure by external approach.  The authors concluded that this preliminary nation-wide survey confirms propranolol high effectiveness against airways' localization of infantile hemangiomas. Propranolol also allows alleviation or cut-off of previous medical treatments. However, recurrences are possible after early treatment interruption.

Guldbakke et al (2010) reported a case and presented a short review of the literature on the use of propranolol used in treatment of infantile hemangioma.  The patient responded quickly to propranolol, with a clinical response within few days.  Literature described reduced size and changes in the color of hemangiomas within 24 to 48 hours.  the authors' experience is in line with that reported in the literature.  Propranolol treatment of this patient group has only been documented in observational studies of small groups and no prospective clinical studies have been reported.  The authors concluded that propranolol seems to be an effective treatment of infantile hemangiomas.  They stated that prospective controlled studies are needed to document optimal dosing, need for monitoring, side effects and duration of therapy.

Georgountzou et al (2012) reported that propranolol, as first-line treatment, yielded excellent results in patients with problematic, proliferative phase infantile hemangiomas (IHs), with very good clinical tolerance and also seems to be effective in relapses.  The investigators administered oral propranolol, a dose of 2 mg/kg/day, to 28 children.  Cardiologic evaluation was performed before treatment initiation.  Hemodynamic variables and blood glucose levels were monitored during the first 24 hours of treatment, while the children were hospitalized.  Clinical response and tolerance were assessed every month, along with photographic documentation.  Macroscopic regression was considered the reduction greater than 90 % in the size of the IHs.  The investigators reported that effects on color and growth were observed within the first month in all cases.  Twenty-four of the 28 subjects completed treatment after a mean duration of 7.56 months, and their hemangiomas were successfully regressed.  Propranolol was administered again, with satisfactory results, in 3 patients (12.5 %) because of hemangioma regrowth.  Satisfactory response was noticeable in ongoing cases.  Episodes of hypotension were noted in 4 patients.  The investigators reported that there were no treatment interruptions because of side effects.  The investigators stated that the optimal duration of propranolol treatment remains to be defined by long-term observation.

Hogeling et al (2011) reported that propranolol hydrochloride, administered orally at 2 mg/kg per day, reduced the volume, color, and elevation of focal and segmental IHs in infants younger than 6 months and children up to 5 years of age.  The investigators randomly assigned 40 children between the ages of 9 weeks and 5 years with facial IHs or IHs in sites with the potential for disfigurement to receive propranolol or placebo oral solution 2 mg/kg per day divided 3 times daily for 6 months.  Baseline electrocardiogram, echocardiogram, and laboratory evaluations were performed.  Monitoring of heart rate, blood pressure, and blood glucose was performed at each visit.  Children younger than 6 months were admitted to the hospital for monitoring after their first dose at weeks 1 and 2.  Efficacy was assessed by performing blinded volume measurements at weeks 0, 4, 8, 12, 16, 20, and 24 and blinded investigator scoring of photographs at weeks 0, 12, and 24.  The investigators reported that IH growth stopped by week 4 in the propranolol group.  The investigators saw significant differences in the percent change in volume between groups, with the largest difference at week 12.  Significant decrease in IH redness and elevation occurred in the propranolol group at weeks 12 and 24 (p = 0.01 and 0.001, respectively).  The investigators reported that no significant hypoglycemia, hypotension, or bradycardia occurred.  One child discontinued the study because of an upper respiratory tract infection.  Other adverse events included bronchiolitis, gastroenteritis, streptococcal infection, cool extremities, dental caries, and sleep disturbance.

Fuchsmann et al (2011) reported the efficacy of propranolol as first-line treatment of head and neck hemangiomas in children and to present an optimized protocol for treating hemangiomas.  A total of 39 children with head and neck infantile hemangiomas were treated.  Propranolol was the sole treatment in 60 % of patients and was started at a mean age of 4.1 months (age range of 1 to 11 months) for early interventions among 33 of 39 patients.  Propranolol therapy resulted in lightening and reduction of hemangiomas at 37 of 39 locations within 2 days to 2 weeks.  One subglottic hemangioma and 1 nasal tip hemangioma did not respond or showed only a partial response; in these patients, propranolol therapy was delayed and followed other treatment failures.  After successful therapeutic regression, 6 recurrences occurred; when re-introduced, propranolol was again effective.  Recurrences were avoided by prolonged treatment.  Twenty-six hemangiomas occurring at locations for which corticosteroid treatment previously would not have been initiated (nose, lips, and parotid area) unless a complication had occurred were treated with propranolol and were rapidly controlled.  The mean duration of propranolol therapy was 8.5 months.  No instances of β-blocker discontinuation because of complications occurred, but propranolol was substituted by acebutolol in 5 patients because of trouble sleeping.  The authors concluded that propranolol is an effective treatment of head and neck infantile hemangiomas, especially when started early within the rapid growth phase, and is first-line treatment of orbit and larynx hemangiomas.  The efficacy and tolerability of propranolol led us to treat some hemangiomas in patients whom we previously would have observed rather than subject to corticosteroid therapy.  Relapse was avoided if treatment was prolonged after theoretical involution (age 12 months).  Questions remain about optimal dosing and age at treatment cessation.

Peridis et al (2011) studied the effectiveness of propranolol in infantile airway hemangiomas and compared the effectiveness of propranolol versus different therapies.  A literature search of Ovid, Embase, the Cochrane database, Google Scholar, and Medline using PubMed as the search engine was performed to identify studies that analyzed the effect of propranolol treatment in children with airway hemangiomas.  Random-effect meta-analytical techniques were conducted for the outcome measures.  A total of 13 studies, comprising 36 patients were included in the analysis.  Propranolol was found to be an effective intervention for the resolution of infantile airway hemangiomas (p < 0.00001).  Meta-analysis of effectiveness of propranolol versus steroids, CO(2) laser, or vincristine showed that propranolol is the most effective treatment.  The authors concluded that this meta-analysis demonstrated that propranolol should be recommended as a first-line treatment in infantile airway hemangiomas.  However, because of the possible side effects of propranolol, current infantile hemangioma treatment centers recommend a full cardiovascular and respiratory review be performed prior to initiation of therapy.

Spiteri Cornish and Reddy (2011) examined the evidence base for the use of propranolol administered orally in the management of peri-ocular capillary hemangioma, and use this information to guide future research.  A systematic review of literature was carried out by 2 independent reviewers using the search strategies highlighted below.  A total of 100 cases of oral propranolol use in peri-orbital or orbital capillary hemangiomas have been documented in the literature.  Of the 85 cases that had details of previous treatment, it was used as first-line treatment in 50 (58.8 %).  The commonest dose used was 2 mg/kg/day.  Adverse events were documented in 1/3 of cases; in most cases these were minor.  Improvement or complete resolution of the lesions occurred in 96 % of cases.  Recurrence was noted in 1/5 of cases.

El-Essawy et al (2011) determined the effectiveness and possible side effects of using propranolol for the treatment of orbital and peri-orbital infantile hemangiomas.  Infants with peri-orbital 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.  A total of 15 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 re-growth (8.3 %) was recorded.  The authors concluded that 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.

Jin et al (2011) prospectively evaluated the safety and effectiveness of propranolol as a first-line treatment for problematic infantile hemangioma in China.  From March 2009 to February 2010, a total of 78 patients with problematic infantile hemangioma were included in the prospective study.  The characteristics of the tumor, including sex, age, site, complications, were recorded.  The response to treatment at 1 week, at 1 month and at the end of treatment was evaluated.  The efficacy of treatment was graded as no response, stabilization, or accelerated regression.  The indications for treatment, side effects and relapse after treatment were documented.  The mean follow-up period was 16.7 months (range of 12.1 to 23.6 months).  Oral therapy was initiated at mean age of 3.7 months (range of 1.1 to 9.2 months) as first-line therapy.  The mean age at the end of treatment was 11.2 months (range of 5.2 to 22.3 months).  The treatment was lasted for 7.6 months (range of 2.1 to 18.3 months).  One week after treatment beginning, the hemangioma growth was controlled in all the patients.  The accelerated regression was achieved in 88.5 % (69/78) of patients after 1 week of treatment, and 98.7 % (77/78) of patients after 1 month of treatment and at the end of treatment.  Ulceration was occurred in 14 cases before treatment, which was healed after treatment for 2 months.  Minor side effects were happened in 15.4 % (12/78) of patients.  Rebound growth of lesion was noticed in 35.9 % (28/78) of patients.  The authors concluded that propranolol is effective in the treatment of infantile hemangioma with minor side effect.  They suggested that propranolol should be used as the first-line treatment.

Bertrand et al (2012) shared their experience using propranolol for problematic IH and to evaluate the efficacy of this treatment modality.  A retrospective chart review analysis was performed for 35 consecutive children treated with propranolol as an oral solution on an outpatient basis in the authors' dermatology/vascular anomalies clinic.  A protocol was established with the help of pediatric cardiologists, including pre-treatment electrocardiography and echocardiography.  Medical photographs taken after 2 months of treatment were rated by 2 independent evaluators.  These researchers treated 31 girls and 4 boys with a median age of 3.5 months.  Rapid improvement was reported in the first days of treatment in 34 patients.  Mean improvement after 2 months was 61.5 %.  No serious adverse effects were reported.  The authors concluded that propranolol was effective in controlling the proliferative phase of problematic IH.  It was well-tolerated in this study.  Outpatient treatment is possible if parents follow strict guidelines.  Propranolol should be a first-line treatment for problematic IH in carefully selected patients.

Mawn (2013) evaluated the potential risks and benefits of the various modalities for peri-ocular IH.  A literature search was conducted for IH and propranolol, steroids, and surgery.  The pertinent published literature on surgical resection of IH were reviewed and summarized.  A retrospective analysis was also performed of the Vanderbilt Children's Hospital (VCH) surgical case series of 12 children who underwent surgical resection of a sight-threatening IH.  A total of 7 articles reported 20 or more patients treated with propranolol for IH.  Many of these patients only had a partial response to propranolol in spite of months of treatment.  In addition to the impact on IH, propranolol has been demonstrated to block neural pathways critical for learning and memory.  Twelve children underwent surgical resection of a visual-threatening IH at VCH.  Two of these children had failed treatment with oral propranolol.  The average time of surgery was 80 minutes.  All 12 children had immediate resolution of the visual compromise.  The authors concluded that early surgical intervention can successfully and quickly result in excellent visual and anatomic outcomes. Propranolol may have unrecognized neurocognitive impact and should be reserved for those lesions unamenable to surgical or local steroid injection.

Gomulka et al (2013) noted that historically the first-line of treatment for IHs has been oral corticosteroids, but because of recent discoveries recognizing the effectiveness of oral and topical beta-blockers, IH management is dynamically changing.  With these new treatment options, some physicians are altering the way they manage IHs despite having little evidence-based data on the treatment methods.  High-lighting treatment changes at a single large tertiary pediatric referral center, the authors concluded that despite the numerous studies already published on this topic, more reliable prospective studies are needed to determine the safety, effectiveness, and best treatment algorithms for the use of topical and oral beta-blockers for the treatment of IHs.

Broeks and colleagues (2013) stated that IHs in the airway may be potentially life-threatening during the proliferative phase.  Available treatments like oral corticosteroids (OCS) and chemotherapeutic agents usually showed variable responses and serious side effects.  Propranolol is a new and promising treatment option.  These investigators reported the findings of a case-series study of 5 IH patients with airway involvement, supplemented with a review of literature.  Propranolol treatment (2.0 to 3.0 mg/kg/day) was initiated between 3 weeks and 6 months of age.  Three cases were treated with propranolol monotherapy, 2 cases with OCS primarily and propranolol secondarily, in which treatment with OCS could be reduced rapidly.  In this case-series study, a dramatic, fast response was observed in all cases, with a permanent effect after discontinuation in 4 cases.  In 1 patient a relapse of airway problems occurred 2 months after discontinuation of propranolol at 16 months of age; this resolved after re-start of propranolol.  Review of literature together with these 5 cases showed 81 patients with airway IHs treated with propranolol.  Propranolol was effective in 90 % of the cases and 7 patients were classified as non-responders.  Eight IHs relapsed while weaning of propranolol or after discontinuation; dose adjustment or re-start was effective in most cases, but 1 patient appeared resistant to therapy.  The authors concluded that propranolol appeared to be a rapidly effective and safe treatment strategy for most IHs obstructing the airway.  Because of the fast and important effects of propranolol, randomized controlled trials are hardly justifiable for this specific, relatively rare but, acute treatment indication.  Despite the effectiveness of propranolol, close monitoring of the patients with an airway IH is needed, considering the risk of relapse of symptoms during or after treatment and the reported resistance to propranolol in at least 9 % of the published cases.  The dose and duration of treatment should be high and long enough to prevent relapse.  They stated that further research should focus on the optimal treatment protocol; the actual percentage of non-responders as well as the mechanism of resistance to propranolol are unknown and need to be ascertained.

Patel and Bauman (2014) stated that "current evidence supports that propranolol is safe to use for otherwise healthy infants with IH with appropriate screening, cautious dosing, and thorough caretaker education following the above-mentioned guidelines.  Outpatient monitored initiation may be considered for infants over 48 weeks post-conceptual age, with adequate social support and without relevant comorbid cardiac, pulmonary, or blood glucose conditions.  For other infants, including those with PHACES (posterior fossa abnormalities, hemangioma, arterial lesions, cardiac and eye anomalies), inpatient initiation is advised".

According to a consensus conference (Drolet et al, 2013), inpatient initiation is recommended for infants who:

• Are less than or equal to 8 weeks (corrected gestational age); or
• Lack adequate social support; or
• Have co-morbid heart, lung, or glucose pathology

For inpatients, propranolol is initiated at 0.33 mg/kg orally 3 times daily (TID); and BP and HR are checked 1 and 2 hours after each administration (Patel and Bauman, 2014).  If 3 doses are tolerated, propranolol is increased to the target of 0.66 mg/kg TID (2 mg/kg/day) with similar BP and HR monitoring.  Once the target dose is tolerated for at least 2 hours, the patient is discharged.  If dose initiation or escalation is not tolerated, the dose is reduced and gradually increased until tolerated.

Outpatient initiation (Drolet et al, 2013) may be considered by experienced physicians for infants who:

• Are greater than 48 weeks post-conceptual age; or
• Have adequate social support; or
• Do not have concerning co-morbid conditions.

Outpatient initiation should be performed with cardiovascular monitoring for at least 2 hours after the first dose and after each escalation to capture peak changes in HR and BP (Patel and Bauman, 2014).  Propranolol is initiated at 0.33 mg/kg, and BP and HR are checked at 1 and 2 hours.  If the initial dose is tolerated, the patient may be discharged on 0.33 mg/kg TID, with a minimum of 6 hours between doses.  Once 0.33 mg/kg TID is tolerated for 3 to 7 days, the dose can be increased to 0.5 mg/kg TID with BP and HR checks at 1 and 2 hours after the first dose.  After 3 to 7 days, the dose may be similarly increased to target dose of 0.66 mg/kg TID with BP and HR checks at 1 and 2 hours after the first dose.

Lymphangiomas are cysts or pockets of lymphatic fluid and can occur anywhere in the body where there are lymphatic vessels, although they are most common in the head and neck, and are sometimes seen in the trunk or axilla.  Cheng published a 2015 systematic review of the use of doxycycline sclerotherapy to treat pediatric head and neck lymphatic malformations. A query of PubMed, EMBASE, and Ovid for studies examining outcomes with doxycycline sclerotherapy as primary treatment with outcomes of 50% or greater reduction retrieved 5 studies.  All studies retrieved were retrospective case series.  Thirty-eight children met the inclusion criteria for analysis, showing successful treatment in 32 (84.2%) treated with doxycycline sclerotherapy, of whom 23 (60.5%) utilizing a single sclerotherapy session.  Average follow-up time was 9.7 months.  Cheng concluded that doxycycline sclerotherapy is very effective for treatment of macrocystic and mixed head and neck lymphatic malformations in children and no associated patient characteristics were found to predict improved success.

Farnoosh et al (2015) stated that lymphatic malformations are congenital vascular anomalies that occur from abnormal development of the lymphatic channels and sclerotherapy can be a reliable alternative to surgery. The authors conducted a retrospective study is to evaluate the safety and efficacy of percutaneous sclerotherapy with doxycycline and 3% Sotradecol as primary treatment for pediatric head and neck lymphatic malformations, as well as to assess outcomes based on lesion classification, location and sclerosant used. Thirty-eight children who underwent percutaneous sclerotherapy of lymphatic malformations in the head and neck region were evaluated and a mean average of 2.9 (range 1-10) sclerotherapy sessions per child were performed. Adequate follow-up data was available for 29 subjects,  with 51.7% demonstrating complete resolution, 27.6% moderate improvement, and 20.7% no response. There was no significant difference in the outcome based on the sclerosant agent used or location of the lesion, but lesion type did affect outcome and macrocystic lesions were found to have a significantly higher resolution rate (95.2%) than microcystic or mixed lesions (p < 0.05). The authors concluded that percutaneous therapy with doxycycline and Sotradecol is safe and effective for children with lymphatic malformations of the head and neck, and that better outcomes were observed with macrocystic lymphatic malformations.

Ardıclı et al (2016) noted that sclerotherapy with bleomycin is an effective treatment for cervical cystic lymphatic malformations in children. They conducted a retrospective study comparing the efficacy of sclerotherapy with surgery for treating extracervical cystic lymphatic malformations in children. Children treated for extracervical cystic lymphatic malformations between 1970 and 2013 were included. The investigators analyzed the records of 70 children (M:F = 1:9) with a mean age of 52.57 ± 54.87 months (range 1-204 months). The number of children treated by surgery alone, sclerotherapy alone, and surgery plus sclerotherapy was 53 (77 %), 13 (18 %), and 4 (5 %), respectively. Results of surgical interventions comprised total excision (n = 41), near-total excision (n = 9), partial excision (n = 6), and incisional biopsy (n = 1) and the complication and recurrence rates were lower, The complete response rate was higher, and the length of hospitalization was shorter in the sclerotherapy group than in the surgery group (5 vs. 15 % and 8 vs. 17 %, respectively, p < 0.05; 91 vs. 77 %, respectively, p = 0.05; and 2.42 ± 1.67 vs. 13.57 ± 16.24 days, respectively, p = 0.03). Thus, the authors concluded that sclerotherapy is as safe as surgery for extracervical macrocystic or mixed lymphatic malformations in children, but is much more effective with higher success rates and lower recurrence rates. Thus, sclerotherapy provides a cost-effective and appropriate mode of treatment for children with extracervical cystic lymphatic malformations. 

Atenolol for the Treatment of Infantile Hemangioma

Ruitenberg and colleagues (2016) noted that (ulcerated) IHs are primarily treated with systemic beta-blockers. Most experience has been obtained with the non-selective beta-blocker propranolol.  Recent studies suggested that atenolol, a selective β1-adrenoreceptor blocker, may be equally effective, but with less side effects than propranolol.  However, studies on atenolol are still scarce and have all been conducted in very small cohorts.

Ng and associates (2016) stated that recent studies have shown that IHs undergo a rapid growth phase between 5.5 and 7.5 weeks of life and do not usually proliferate beyond 6 months; growth thereafter is usually proportionate to the child's growth.  These investigators evaluated the evidence for topical timolol as primary monotherapy for cutaneous facial IHs before 12 months of age, and determined the differences in outcome between early (before 6 months) and late initiation (after 6 months) of timolol.  A review of English language articles published up to November 2015 was performed using selected key words.  Articles identified were further reviewed for relevance.  The full text of studies included for final analysis was perused to include pertinent patient details, treatment protocol with timolol, complications (if any) reported, and response to treatment.  A total of 4 studies met the inclusion criteria.  In children before 12 months of age, the effectiveness of topical timolol for the treatment of cutaneous facial IHs in achieving clinically significant improvement as defined by a standardized Global Assessment Score of 3 and above ranged from 47 % to 88 %.  One study also showed that IH regression was greater in patients started on timolol before 6 months of age compared with those started later (p < 0.05).  The authors concluded that topical timolol initiated in children before 12 months of age appeared to be safe and clinically effective.  However, there was insufficient data for detailed analysis of outcomes in patients who commenced treatment before and after 6 months of age.

The Agency for Healthcare Research and Quality’s guideline on "Management of infantile hemangioma’ (20160 did not mention timolol as a therapeutic option.

In a review on IH, Leaute-Labreze and co-workers (2017) stated that the main indications for treatment are life-threatening IH (causing heart failure or respiratory distress), tumors posing functional risks (e.g., visual obstruction, amblyopia, or feeding difficulties), ulceration, and severe anatomic distortion, especially on the face.  Oral propranolol is now the first-line treatment, which should be administered as early as possible to avoid potential complications.  Hemangioma shrinkage is rapidly observed with oral propranolol, but a minimum of 6 months of therapy is recommended.  Timolol was not mentioned as a therapeutic option.

In a systematic review and meta-analysis, Khan and colleagues (2017) evaluated all published data on the safety and effectiveness of topical timolol in the treatment of IH.  A total of 31 studies with 691 patients were included.  The fixed effects pooled estimate of the response rate defined as any improvement from baseline of IH after treatment with topical timolol was significant (RR = 8.96; 95 % CI: 5.07 to 15.47; heterogeneity test p = 0.99), and the treatment was well-tolerated.  However, the quality of evidence was low-to-moderate.  The authors concluded that topical timolol is an effective treatment for small IH, with no significant adverse effects noted; however, there is still a need for adequately powered randomized controlled trials (RCTs).

Wang and colleagues (2019) noted that several studies have reported their experience in using oral atenolol in patients with IH, especially as an alternative to propranolol; however, the safety and efficacy of oral atenolol has not been evaluated.  These investigators searched PubMed (Medline), Central, Embase, Web of Science and EBSCOhost (until May 2018) for the eligible studies reporting more than 10 IH patients who were treated with oral atenolol with detailed original data, including outcomes, regimens and adverse events (AEs).  The data was standardized and analyzed by using R software with meta-package.  A total of 9 of 141 identified articles, including 341 IH patients treated with oral atenolol therapy, were included.  The pooled response rate of atenolol was 0.90 (95 % CI: 0.85 to 0.93), and the rebound rate was 0.11 (95 % CI: 0.08 to 0.16).  Among the 341 patients, 44 patients were switched to atenolol therapy from propranolol due to AEs.  The response rate of subsequent atenolol treatment was 90.9 % (40/44).  Regarding AEs, 141 patients reported 177 episodes of AEs, and the pooled rate was 0.26 (95 % CI: 0.12 to 0.47).  Gastro-intestinal symptoms (e.g., constipation, diarrhea and vomiting) were the most frequent AEs (22.6 %).  Widely known propranolol-related AEs, including hypoglycemia, bronchospasm, bradycardia and hypotension, were not recorded.  The authors concluded that atenolol appeared to be a safe and effective therapy for the treatment of IH; and may be a promising alternative to propranolol.

Chen et al (2023) noted that although propranolol has been established as the gold standard when treatment is sought for infantile hemangioma (IH), concerns over its side effect profile have led to increasing usage of atenolol.  These researchers carried out a systematic review of PubMed, Scopus, CINAHL, Google Scholar, and Cochrane following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines using MeSH terms and keywords for the terms of propranolol, atenolol, and infantile hemangioma, including alternative spellings.  All RCTs or cohort studies directly comparing outcomes of hemangioma treatment with atenolol and propranolol were included.  They carried out a meta-analysis with pooled mean differences (MDs), pooled odds ratios (ORs), and analysis of proportions.  A total of 669 participants in 7 studies (3 RCTs and 4 cohort) were included.  Propranolol showed a significantly higher rate of complete response compared to atenolol (73.3 % versus 85.4 %, p = 0.0004).  The pooled MD of 0.07 (95 % CI: -0.12 to 0.27) in Hemangioma Activity Score (HAS) was not statistically significant.  In terms of side effects, there were significantly more agitation and bronchial hyperreactivity events in the propranolol group (p = 0.0245 and p < 0.0001, respectively).  Overall, there was a significantly greater number of AEs in the propranolol group compared to the atenolol group (185 versus 117, p < 0.00001).  The overall pooled OR was 2.70 (95 % CI: 1.90 to 3.84), indicating that there were 2.7 times higher odds of AEs in the propranolol group.  The authors concluded that propranolol treatment resulted in a significantly higher rate of complete response than atenolol; however, its use must be weighed against its greater side effect profile.

Pattanshetti et al (2022) stated that IH is the most common benign vascular tumor of infancy.  Propranolol is considered 1st-line therapy for IH; however, it is associated with side effects.  Thus, there was a need for alternative therapy; atenolol may be free from such side effects.  In a systematic review and meta-analysis, these investigators developed a more accurate estimate of the safety and effectiveness of atenolol compared to propranolol in the treatment of IH.  They carried out a search of various literature databases (PubMed, Embase, Ovid, Scopus, Cochrane Central, CINAHL, Web of Science, and Google Scholar) to identify studies that compared propranolol versus atenolol in the treatment of IH.  The combined odds ratio (OR) along with corresponding 95 % confidence intervals (CIs) were evaluated using a fixed-effects model.  A total of 300 studies were screened of which 5 including 116 patients in atenolol-arm and 138 patients in the propranolol-arm were analyzed.  Atenolol was comparable to propranolol in terms of effectiveness as no significant difference was observed between both treatment arms in terms of hemangioma activity score (mean difference [MD] of 0.25 [95 % CI: -0.21 to 0.71]) and complete response (OR = 0.43; 95 % CI: 0.17 to 1.11; p = 0.08,).  Atenolol therapy was better than propranolol in terms of safety, i.e., serious/potentially serious side effect, (OR = 0.11; 95 % CI: 0.02 to 0.51; p = 0.005) and wheezing/bronchial hyperreactivity (OR = 0.11; 95 % CI: 0.02 to 0.51; p = 0.005).  The authors concluded that the findings of this meta-analysis provided evidence that atenolol exhibited a comparable effectiveness and better safety profile with propranolol.  Moreover, these researchers stated that large, multi-center, and well-designed RCTs are needed to draw an exact conclusion regarding the safety and effectiveness of atenolol in treating IH compared to propranolol.

The authors concluded that this study had several drawbacks.  To conclude that atenolol was better than propranolol in terms of safety and effectiveness, the quality of the study design chosen was quite important.  Limitations in all studies were small number of subjects and long-term follow-up was lacking; RCTs are the best to include in a meta-analysis.  A key, but the unavoidable drawback was the heterogeneity of the studies included in the study.  Due to the lack of enough RCTs, these researchers had to include RCTs as well as prospective and retrospective study designs.  There was lack of adequate studies regarding the effect of different doses of atenolol in treating IH.  There was inadequate data regarding the exact age to initiate the therapy, optimal dosage and duration of therapy as well as the criteria for discontinuing the therapy.

Combination of Propranolol and Pulsed Dye Laser for the Treatment of Infantile Hemangioma

Rodríguez-Ruiz et al (2016) stated that ulceration is the most common complication of IHs, with 15.8 % of them usually appearing in the proliferative phase. These investigators presented their experience in the treatment of ulcerated IHs with the combination of pulsed dye laser (PDL) and propranolol.  These researchers performed a retrospective observational study on patients with ulcerated IHs treated with PDL in association with propranolol.  The study included 7 patients, 3 cases in labial area and 4 cases in the nappy area.  A review was also performed on a historical cohort of 5 children with ulcerated hemangiomas with the same features, but treated only with propranolol, topical agents and occlusive dressings.  The median size of the ulcer was 1.0 cm, and there was a mean time of onset pre-treatment of 2 weeks.  Pain and bleeding was present in all patients.  After 2 weeks of combined propranolol and PDL treatment, all lesions were healed.  The pain disappeared after the first laser session.  Patients with ulcerative hemangioma in the labial area obtained a better response than patients with hemangioma in the nappy area.  The cohort of patients treated with propranolol required a mean healing time of 5.2 weeks, with the addition of an occlusive dressing with ointment.  The authors concluded that the findings of this study suggested that combined PDL and propranolol had synergistic effects that accelerated the healing of ulcerated hemangioma.  Moreover, they stated that further studies with larger numbers of patients are needed to confirm this fact.

Chinnadurai et al (2016) reviewed studies of laser treatment of IH. These investigators searched multiple databases including Medline and Embase from 1982 to June 2015.  Two investigators independently screened studies against pre-determined criteria and extracted key data.  Investigators independently assessed study risk of bias and the strength of the evidence of the body of literature.  These researchers identified 29 studies addressing lasers: 4 randomized controlled trials (RCTs), 8 retrospective cohort studies, and 17 case series.  Lasers varied across studies in type, pulse width, or cooling materials.  Most comparative studies (n = 9) assessed variations of PDL and examined heterogeneous end-points.  Most studies reported on treatment of cutaneous lesions.  Overall, longer pulse PDL with epidermal cooling was the most commonly used laser for cutaneous lesions; Nd:YAG was the most commonly used intralesionally.  Most studies reported a higher success rate with longer pulse PDL compared with observation in managing the size of IH, although the magnitude of effect differed substantially.  Carbon dioxide (CO2) laser was used for subglottic IH in a single study, and was noted to have a higher success rate and lower complication rate than both Nd:YAG and observation.  Studies comparing laser with β-blockers or in combination with β-blockers reported greater improvements in lesion size in combination arms versus β-blockers alone and greater effects of lasers on mixed superficial and deep IH.  Strength of the evidence for outcomes after laser treatments ranged from insufficient to low for effectiveness outcomes.  Strength of the evidence was insufficient for the effects of laser compared with β-blockers or in combination with β-blockers as studies evaluated different agents and laser types.  Studies assessing outcomes after CO2 and Nd:YAG lasers typically reported some resolution of lesion size, but heterogeneity among studies limited these researchers’ abilities to draw conclusions.  The authors concluded that studies of laser treatment of IH primarily addressed different laser modalities compared with observation or other laser modalities.  Pulsed dye laser was the most commonly studied laser type, but multiple variations in treatment protocols did not allow for demonstration of superiority of a single method.  Most studies reported a higher success rate with longer pulse PDL compared to observation in managing the size of IH, although the magnitude of effect differed substantially.  Studies generally found PDL more effective than other types of lasers for cutaneous lesions.  When first introduced as a primary treatment for IH, various laser modalities generally offered superior outcomes compared with steroid therapy and observation.  Moreover, they noted that in the era of β-blocker therapy, laser treatment may retain an important role in the treatment of residual and refractory lesions.

Topical Timolol, Alone or In Combination with Propanolol

Jha and associates (2015) stated that IH is the most common benign vascular tumor of childhood that has a tendency for spontaneous involution. These investigators evaluated the effectiveness of topical timolol maleate in the treatment of superficial IHs and associated side effects during the course of treatment.  A total of 4 boys and 5 girls with a median age of 5 months were reviewed at 2-week intervals for a period of 16 weeks.  A decrease in size, color, and consistency were noted.  Adverse effects caused by timolol maleate were noted and managed.  Of the 9 cases, 2 patients showed excellent response, 5 showed good response, 1 showed partial response, and 1 had poor response.  The authors concluded that topical timolol maleate is safe and effective in the treatment of IHs.  These preliminary findings need to be validated by well-designed studies.

In an observational study, Xu and colleagues (2015) evaluated the clinical effects and safety of topical timolol maleate for the management of superficial IHs. From October 2012 to March 2014, a total of 35 infants (24 girls and 11 boys; 2 to 10 months old; median age of 4.7 months) with superficial hemangiomas were treated with the local application of timolol maleate in the authors' department; 35 lesions were treated using topically administrated timolol maleate every 12 hours for a mean duration of 22 weeks (range of 6 to 45 weeks).  Follow-up visits were scheduled monthly and changes in tumor size, texture, and color were recorded.  Treatment response was scored according to a 3-point scale system as good, partial, or no response.  Adverse effects after medication were evaluated and managed accordingly.  All patients completed treatment.  Of the 35 hemangiomas, 18 (51.4 %) showed a good response, 10 (31.4 %) showed a partial response, and 6 (17.2 %) had no response.  The total response rate was 82.8 % (29 of 35).  Clinically, no systemic or local side effects caused by timolol maleate were observed in the patients.  The authors concluded that topical timolol maleate could provide a safe and effective alternative to the systemic use of propranolol for the treatment of superficial IHs.  Moreover, they stated that further prospective studies are needed to confirm the safety and effectiveness of topical timolol maleate for the treatment of IHs.

In a retrospective study, Ge and co-workers (2016) examined the safety and effectiveness of combined therapy of oral propranolol and topical timolol in the treatment of IHs.  A total of 89 infants with compound IHs were treated with oral propranolol 2 mg/kg/day divided 2 times per day and timolol maleate 0.5 % gel 3 times per day, for at least 3 months.  Two observers evaluated the hemangioma independently at 0, 1, 3, 6, 9 months after the initiation of treatment.  Changes in the hemangioma score values were evaluated using paired t-test.  Rebound growth and adverse effects were recorded.  After treatment was completed, this combined therapy achieved clinical response in 100 % of the patients (89/89).  Significant positive effects were demonstrated at 1, 3, 6 months (p < 0.001), but not obvious after 6 months (p = 0.06).  The response of IHs to the therapy was dependent on the age at initial treatment.  The average treatment duration was 6.48 (5.77 to 7.19) months.  One patient (1.1 %) relapsed after cessation of 6-month treatment, and 7 children (7.8 %) developed side effects.  The authors concluded that the findings of this study suggested that oral propranolol combined with topical timolol treatment was very effective and well-tolerated for compound IHs, which can be used as a first line treatment.  These preliminary findings need to be validated by well-designed studies.

Pigment Epithelium-Derived Factor (PEDF)

Li and colleagues (2017) noted that in previous studies, the expression and the role of proangiogenic factors in IHs have been well studied.  However, the role of angiogenic inhibitors has been revealed rarely.  The expression of pigment epithelium-derived factor (PEDF), as the strongest and safe endogenous inhibitor, is still unrecognized.  To investigate the expression and significance of the PEDF in the proliferating and regressing phases of IHs, these researchers examined the expression of PEDF, vascular endothelial growth factor (VEGF), Ki-67 (also known as MKI67) , and CD34 protein in hemangioma tissues with immuno-histochemical polymer HRP method in 42 cases during the proliferative phase, 40 cases during the regressing phase, and 11 cases of non-involuting congenital hemangiomas (NICHs).  Meanwhile, the mRNA expression of these factors was detected with quantitative real-time polymerase chain reaction (RT-PCR).  These investigators found the protein and mRNA expression of PEDF in regressing phase was significantly higher than those in proliferative phase and NICHs (p < 0.001), while the protein and mRNA expression of VEGF were much lower (p < 0.001).  The micro-vessel density (MVD), Ki-67 changes, and the expression of PEDF and VEGF were found significantly correlated.  The authors concluded that these findings indicated that the reduction of VEGF and increase in PEDF were causative to the evolution of IH; PEDF may play a key role in the spontaneous regression of IH and may become an important potential therapeutic agent for IH.

Endothelial and Circulating C19MC microRNAs as Biomarkers of Infantile Hemangioma

Strub and colleagues (2016) stated that IH is the most common vascular tumor of infancy, and it uniquely regresses in response to oral propranolol.  MicroRNAs (miRNAs) have emerged as key regulators of vascular development and are dysregulated in many disease processes, but the role of miRNAs in IH growth has not been investigated.  These investigators reported expression of C19MC, a primate-specific mega-cluster of miRNAs expressed in placenta with rare expression in post-natal tissues, in glucose transporter 1-expressing (GLUT-1-expressing) IH endothelial cells and in the plasma of children with IH.  Tissue or circulating C19MC miRNAs were not detectable in patients having 9 other types of vascular anomalies or unaffected children, identifying C19MC miRNAs as the first circulating biomarkers of IH.  Levels of circulating C19MC miRNAs correlated with IH tumor size and propranolol treatment response, and IH tissue from children treated with propranolol or from children with partially involuted tumors contained lower levels of C19MC miRNAs than untreated, proliferative tumors, implicating C19MC miRNAs as potential drivers of IH pathogenesis.  The authors concluded that detection of C19MC miRNAs in the circulation of infants with IH may provide a specific and non-invasive means of IH diagnosis and identification of candidates for propranolol therapy as well as a means to monitor treatment response.  They stated that validated targets of C19MC miRNAs suggested testable hypotheses regarding the mechanisms of IH pathogenesis and the accelerated regression with propranolol therapy.  These preliminary findings need to be validated by well- designed studies.

Serum Vascular Endothelial Growth Factor as a Biomarker of Infantile Hemangiomas

Paria and colleagues (2018) noted that although IHs are the most common benign tumor of infancy, their etiopathogenesis is not fully understood.  Some studies reported a diagnostic role for vascular endothelial growth factor (VEGF), but such studies are lacking from India.  These investigators studied the clinicoepidemiological profile of His and compared the serum levels of VEGF in IHs and controls, and determined correlations between serum levels of VEGF and growth characteristics of IHs.  A hospital-based, cross-sectional study was carried out on 30 clinically diagnosed cases of IH and 30 controls presenting with other disorders; VEGF levels were recorded for both cases and controls by the sandwich enzyme-linked immunosorbent assay (ELISA) technique.  Results were analyzed using SPSS version 20.0, and their significance determined using appropriate tests.  Mean serum VEGF level in the cases was 216.8 ± 49.2 pg/ml while in the control group it was 115.1 ± 43.1 pg/ml (p < 0.0001).  There were no statistically significant correlations between serum VEGF levels and sex or size, phase of growth, morphological variants or ulceration of lesions.  The authors concluded that the mean value of serum VEGF in the study group was significantly higher than that in the control group, suggesting that serum VEGF could serve as a diagnostic marker of IH.  Mean serum VEGF was higher in proliferative lesions than in involuting lesions, indicating that it may also be useful as a prognostic serological marker in cases of IH.  These researchers noted that based on the findings of this study and published literature, they recommended that further studies be conducted, including larger numbers of cases, to study the levels of serum VEGF in cases of IH and their correlations with various parameters.  The main drawback of this study was that the sample size was not large enough to draw clinically applicable conclusions.  An adequate sample size could not be achieved because of low incidence of the disease, and resource and time constraints.  Furthermore, correlations between the volume of IHs and VEGF levels could not be looked at due to a lack of resources for lesional volume measurements.

Treatments for Orbital Lymphangioma

Patel and colleagues (2019) stated that orbital lymphangiomas are a subset of localized vascular and lymphatic malformations, which most commonly occur in the head and neck region.  Orbital lymphangiomas typically present in the first decade of life with signs of ptosis, proptosis, restriction of ocular motility, compressive optic neuropathy, and disfigurement.  Thus, early and effective treatment is crucial in preserving vision.  Due to proximity to vital structures, such as the globe, optic nerve, and extra-ocular muscles, treatment for these lesions is complicated and includes a large array of approaches including observation, sclerotherapy, systemic therapy, and surgical excision.  Of these options, there is no clear gold standard of treatment.  These researchers examined the evidence supporting medical and surgical interventions for the reduction / treatment of orbital lymphangiomas in children and young adults.  They searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2018, Issue 5); Ovid Medline; Embase.com; PubMed; Latin American and Caribbean Health Sciences Literature Database (LILACS); ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP).  They did not use any date or language restrictions in the electronic search for trials.  These researchers last searched the electronic databases on May 22, 2018.  They planned to include RCTs comparing at least 2 of the following interventions with each other for the treatment of orbital lymphangiomas: observation; sildenafil therapy; sirolimus therapy; sclerotherapy; surgery (partial or complete resection).  They planned to include trials that enrolled children and adults up to 32 years of age, based on a prior clinical trial protocol.  There were no restrictions regarding location or demographic factors.  Two review authors independently screened the titles, abstracts, and full articles to evaluate their suitability for inclusion in this review.  No risk of bias or data extraction was performed because these investigators did not find any trials for inclusion.  If there had been RCTs, 2 authors would have assessed the risk of bias and abstracted data independently with discrepancies being settled by consensus or consultation with a third review author.  There were no RCTs that compared any 2 of the mentioned interventions (medical or surgical) for treating orbital lymphangiomas in children and young adults.  The authors concluded that  there are currently no published RCTs of orbital lymphangioma treatments.  Without these types of studies, conclusions could not be drawn regarding the effectiveness of the medical and surgical therapeutic options for patients with orbital lymphangiomas.  The presence of only case reports and case series on orbital lymphangiomas made it clear that RCTs are needed to address the differences between these options and help guide treatment plans.  Such trials would ideally compare outcomes between individuals randomized to one of the following therapeutic options: observation, sclerotherapy, systemic sirolimus therapy, systemic sildenafil therapy, and surgical excision.

Nadolol Versus Propranolol in the Treatment of Infants with Infantile Hemangioma

Pope et al (2022) noted that propranolol for IH has been shown to be effective and relatively safe; however, other less lipophilic β-blockers, such as nadolol, may be preferable in individuals who experience propranolol unresponsiveness or AEs.  In a prospective, double-blind non-inferiority study with a non-inferiority margin of 10 %, these researchers documented the non-inferiority and safety of oral nadolol compared with oral propranolol in infants with IH.  This trial compared propranolol with nadolol in infants aged 1 to 6 months with problematic IH.  The study was carried out in 2 academic pediatric dermatology centers in Canada between 2016 and 2020.  Subjects were infants aged 1 to 6 months with a hemangioma greater than 1.5 cm on the face or 3 cm or greater on another body part causing or with potential to cause functional impairment or cosmetic disfigurement.  Participants received oral propranolol and nadolol in escalating doses up to 2 mg/kg/day.  Main outcome measures included between-group differences comparing changes in the bulk (size and extent) and color of the IH at week 24 with baseline using a 100-mm visual analog scale (VAS).  The study included 71 patients.  Of these, 36 were treated with propranolol.  The mean (SD) age in this group was 3.1 (1.4) months, and 31 individuals (86 %) were female; 35 infants were treated with nadolol.  The mean (SD) age in this group was 3.2 (1.6) months, and 26 individuals (74 %) were female.  The difference in IH between groups by t-test was 8.8 (95 % CI: 2.7 to 14.9) for size and 17.1 (95 % CI: 7.2 to 30.0) for color in favor of the nadolol group, demonstrating that nadolol was non-inferior to propranolol.  Similar differences were noted at 52 weeks: 6.0 (95 % CI: 1.9 to 10.1) and 10.1 (95 % CI: 2.9 to 17.4) for size and color improvement, respectively.  For each doubling of time unit (week), the coefficient of involution was 2.4 (95 % CI: 0.5 to 4.4) higher with nadolol compared with propranolol.  Safety data were similar between the 2 interventions.  The authors concluded that oral nadolol was non-inferior to oral propranolol, indicating it may be a safe and effective alternative in cases of propranolol unresponsiveness or AEs, or when faster involution is needed.  Moreover, these researchers stated that although nadolol showed a faster and better response in patients with problematic IHs, further studies are needed to prove superiority over propranolol.

The authors stated that this study had several drawbacks.  First, although VASs have been used in several cohort studies, they remain a subjective outcome measure.  Second, recruitment was stopped short of 5 patients for feasibility reasons; however, given these findings, further recruitment would have unlikely affected the results.  Third, randomization was not carried out according to the hemangioma subtype, which may have introduced a response bias.

Sirolimus for the Treatment of Diffuse Intestinal Infantile Hemangioma

Kleinman et al (2023) reported on the case of a 3-month-old female with cardiovascular anomalies and diffuse intestinal infantile hemangioma (IIH) of the small bowel suggesting possible diagnosis of PHACE syndrome (posterior fossa anomalies, hemangioma, arterial lesions, cardiac abnormalities/coarctation of the aorta, eye anomalies).  The gastro-intestinal (GI) symptoms persisted under treatment with propranolol, whereas the addition of sirolimus led to regression of the IIH.  These investigators carried out a systematic review using PubMed, Embase, and Ovid Medline databases between 1982 and 2021.  A total of 4,933 studies were identified; 24 met inclusion criteria with 46 IIH cases.  The most common GI presentations were unspecified GI bleed (40 %) and anemia (38 %).  The most common treatments were corticosteroids (63 %), surgical resection (32.6 %), and propranolol (28 %).  Available outcomes were primarily bleeding arrest (84 %).  A total of 9 cases (19.5 %) were diagnosed with definite PHACE, 5 (11 %) with possible PHACE, and 32 (69.5 %) no PHACE.  This case presented with symptoms most consistent with those of possible PHACE and definite PHACE.  No cases in this review underwent treatment with sirolimus.  The authors concluded that this was the 1st reported case of successful treatment of IIH with sirolimus.  This preliminary finding needs to be validated by well-designed studies.

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References