Vascular LesionsPropranolol treatment of HOI

DR. ALI MANSOURENT DEPARTMENT ALMOWASSAT HOSPITAL

DiagnosisA GOOD DIAGNOSIS = BEST TREATMENT

Overview

• Vascular lesions of the head and neck encompass a wide range of different lesions

• Historically, these lesions have been poorly understood, and their nomenclature reflects this

• Over the years, this nomenclature has evolved as progress has been made in our understanding of the histopathology, clinical behavior, treatment, and prognosis of these lesions

classifications

Vascular lesionVascular tumor

Vascular Anomalie

DDx

Vascular tumors grow mainly by endothelial cell hyperplasia whereas vascular malformations have a quiescent endothelium (inner lining) and are considered

localized defects of vascular morphogenesis

subclassificationsTumors

hemangioma

Congenita

l

RICH

NICH

Infant

Focal -

segmental

Superficia

l - Deep

pyogenic

granuloma

KHE TA Hemangiopericytoma Angiosarcoma

KHE’ Kaposiform hemangioendothelioma TA’ Tufted angioma RiCH’ Rapidly involutingNiCH’ Noninvoluting

subclassificationsAnomalie

Single-Vessel Type

Capillary Venous Arteriovenous

Lymphatic

macrocystic

microcystic

Combined

lymphaticovenous

hemangioma

Capillary

Venous

Lymphatic

Arteriovenous

It seems difficult to Diagnose VL?

THE KEY FOR BEST DIAGNOSIS

The Key

History clinical observation Physical examination Echo + Doppler MRI Rarely Biopsy _+  immunohistochemistry

General Consideration

Vascular Malformations Vascular Tumor Congenital abnormality 70% apparent during first few weeks

proportional growth Proliferative

No gender predilection Female to male ratio 3:1

expand secondary to sepsis, trauma, or hormonal changes- Do not involute

Rapid postnatal growth followed by slow involution

Normal endothelial cell turnover Endothelial cell proliferation

No response to corticosteroids respond dramatically to corticosteroid

Low-flow: phleboliths, ectatic channels Echo-MRI – High Flow on proliferative phase

High-flow: enlarged, tortuous vessels with arteriovenous shuntingImmunonegative for hemangioma biologic markers

Immunopositive for biologic markers (including GLUT1)

Hemangioma of infantPRESENTATION - TREATMENT

Hemangioma

Infantile hemangiomas are benign vascular tumors characterized by the proliferation of the endothelial cells

Hemangiomas represent the most common tumor in infants, occurring in up to 3-5% of all children

Most hemangiomas affect the head and neck

Clinical Presentation

manifest as an isolated, dark lesion of the skin HOIs are absent at birth and appear in infancy They proliferate for 6 to 9 months and involute partially or 

completely over several years complete involution occurs in 50% of lesions by age 5 years and

in 70% of lesions by age 7 years Vascular lesions that do not follow this pattern should be 

considered for alternative diagnose F\M 3\1 – more common on premature infants - more common

in whites

Detection of GLUT-1 in HOI endothelium distinguishes them from other vascular anomalies

Improvements in image acquisition with both computed  tomography (CT)  and (MRI) allow differentiation between HOIs and other vascular anomalies

Congenital hemangioma

Other hemangiomas present at birth are already mature and do not proliferate. These are referred to as congenital hemangiomas and are divided into

rapidly involuting congenital hemangiomas (RICHs) noninvoluting congenital hemangiomas (NICHs) Most cases of RICH involute entirely by age 1 year. NICHs do not decrease in size. Congenital hemangiomas account for approximately 3% of all

hemangiomas GLUT-1 negative

Superficial vs Deep

Superficial lesions  50% to 60% that affect the skin manifest as raised, red lesions that are somewhat firm to the touch

Subcutaneous lesions 15% tend to manifest as deeper masses with a blue hue and an unaffected overlying skin layer

Mixed 25-35% These deeper lesions are more difficult to differentiate from

vascular malformations and other masses and more often require radiographic imaging to aid in diagnosis

Focal vs Segmental

Focal Located on the bony prominences Segmental Cover 1 or more segments of the face and body Segmental HOIs are usually superficial, variably involve

cutaneous dermatomes, and have more associated morbidity than focal HOI specially PHACES Syndrom

Multifocal In children with 5 or more hemangiomas, the workup should include an abdominal ultrasound to evaluate

for visceral hemangiomas

PHACESSyndrome

Posterior fossa intracranial abnormalitie Hemangiomas Arterial abnormalities Cardiac defects and coarctation of the  aorta Eye  abnormalities Sternal  clefting

About 20% of segmental infantile hemangioma are associated with PHACE syndrome—88% of which are females

Special Sites

Periorbital hemangioma cause significant problems with vision, especially during the

proliferative phase and slow involution amblyopia affects approximately 75% of children over the age of 1 year who were untreated.

subglottic hemangioma Cause airway compromise may prove fatal – may require

Tracheotomy Auditory canal obstruction Lips

COMPLICATIONS 12%

Local Ulceration and infection ScarringPermanent Disfigurement or Scarring Can Occur if Left Untreated1/3 of facial infantile hemangiomas will result in soft tissue distortion or damage69% of infantile hemangiomas leave residual lesions when left untreated Systemic Congestive heart failure may occur in the setting of large and/or multiple

hemangiomas located in the skin, subcutaneous tissues, or viscera Kasabach-Merritt phenomenon this phenomenon is not associated with

infantile hemangiomas

ulceration

Treatment indication

Treatment is indicated when functional or cosmetic complications arise (or are predicted to arise) that are worse than the side effects of intervention.

Lesion size, location, patient age, and phase of the lesion (proliferative, involuting, mature) also influence the method and timing of intervention

Side effects

Treatment Options

Observation Medical therapy Propranolol – Corticosteroid (injection-Systemic) – INF -

vincristine. Laser therapy pulsed -dye laser (PDL)- (CO2) laser - Nd:YAG Surgical therapy

History of propranolol

While treating French children for congenital disease supraventricular tachycardia in 2008,

Dr. Christine Léauté-Labréze and her colleagues discovered that propranolol hydrochloride could also control the growth of hemangiomas. It is believed that the drug may have an effect on proliferating infantile hemangiomas through vasoconstriction, inhibition of angiogenesis, and induction of apoptosis In 2014 this Drug had FDA approved to treat HOIProven Efficacy 60% of infantile hemangioma completely or nearly completely resolved by 6 months vs 4% for placebo88% of infantile hemangioma showed improvement after 5 weeks of treatment

Propranolol in general

Propranolol is a synthetic, b-adrenergic receptor-blocking agent that is classified as nonselective because it blocks bothb-1 and b-2 adrenergic receptors - inhibition of renin release by the kidneys

resulting in a decrease in heart rate (HR) and blood pressure (BP)

first-pass metabolism by the liver with only∼25% of oral propranolol reaching the systemic circulation. Multiple pathways in the cytochrome P450 system are involved in propranolol’s metabolism, making clinically important drug interactions a potential issue

Mechanism of Action Hypothesis

The mechanism of action of HEMANGEOLTM (propranolol hydrochloride) in infantile hemangioma is not known.

The hypothesis is that the drug’s effect on proliferating infantile hemangioma can be attributed to 3 molecular mechanisms, leading to:

1. A local hemodynamic effect (reduction in blood flow)2. An anti-angiogenic effect (reduction of growth factors)3. An apoptosis triggering effect on capillary endothelial cells

(increase rate of infantile hemangioma cell death)

there is significant uncertainty and divergence of opinion regarding

1. pretreatment evaluation 2. safety monitoring 3. dose escalation4. use in PHACE syndrome

pretreatment evaluation

Pretreatment ECG - Echo

a more indication-driven ECG strategy is likely to develop because the incidence of ECG abnormalities that would limit propranolol use in children with IH appears low

congenital complete heart block is rare, with an estimated prevalence of 1 in 20 000 live births, and this is most commonly associated with maternal connective tissue disease

Because structural and functional heart disease have not been associated with uncomplicated IH, echocardiography as a routine screening tool before initiation of propranolol is not necessary in the absence of abnormal clinical findings

ECG Indications

ECG should be part of the pretreatment evaluation in any child when

the HR is below normal for age 1. newborns (<1 month old),<70 beats per minute,2. infants (1–12 months old), <80 beats per minute, and3. children (more 12 months old): <70 beats per minute family history of congenital heart conditions or arrhythmias or

maternal history of connective tissue disease history of an arrhythmia or an arrhythmia is auscultated during

examination

contraindicated

premature infants with corrected age < 5 weeks infants weighing less than 2 kg infants with known hypersensitivity to propranolol or any of the

excipients infants with asthma or history of bronchospasm heart rate < 80 beats per minute greater than first-degree heart block decompensated heart failure blood pressure < 50/30 mm Hg pheochromocytoma

Administration - recommended Dosing   initiated in infants aged 5 weeks (more than 2kg) to 5 months.

 should be given to infants during or right after a feeding Dose between 1-3 mg\kg Week 1 – starting dose is 0.15 mL/kg (0.6 mg/kg) twice daily Week 2 – increase dose to 0.3 mL/kg (1.1 mg/kg) twice daily Week 3 – increase to a maintenance dose of 0.4 mL/kg (1.7 mg/kg) twice

daily Administer twice daily doses at least 9 hours apart during or after feeding

The dose of  should be skipped if the infant is vomiting or not eating Monitor heart rate and blood pressure for 2 hours after the first dose or

increasing dose Duration of treatment: 6 months

Mean age at treatment initiation was 3.6 months. Mean dose  was 2.2 mg/kg/day. Mean treatment duration was 7.1 months.

Side effects

The following adverse events were observed with incidence of less than 1% Cardiac disorders -Decreased blood glucose-Decreased heart beat-

Alopecia-Urticaria The most common adverse reactions  (occurring ≤10% of

patients): Sleep disorders Aggravated respiratory tract infections Diarrhea Vomiting

Fewer than 2% of patients discontinued treatment due to adverse reactions

Bradycardia and Hypotension

Propranolol’s effects on BP and HR in children peak around 2 hours after an oral dose

During initiation of propranolol for IH in infants, bradycardia (<2 SD of normal) and hypotension (<2 SD of

normal) after the first dose (2 mg/kg/day divided 3 times daily) were infrequent and asymptomatic

Hypoglycemia

Symptomatic hypoglycemia and hypoglycemic seizures have been reported in infants with IH treated with oral propranolol

often associated with poor oral intake or concomitant infection

Nonselective b-blockers, such as propranolol, may block catecholamine induced glycogenolysis, gluconeogenesis, and lipolysis, predisposing to hypoglycemia

patients with IH may be at increased risk if they have received or are concomitantly receiving treatment with corticosteroids, because adrenal suppression may result in loss of the counterregulatory cortisol response and increase the risk of hypoglycemia

With propranolol-induced b-adrenergic blockade, early symptoms may be masked. Therefore, because sweating is not typically blocked by b-blockers, this may be a more reliable symptom for diagnosis

Bronchospasm

Bronchial hyperreactivity, described as wheezing, bronchospasm, or exacerbation of asthma/bronchitis, is a recognized side effect of propranolol as the result of its direct blockade of adrenergic bronchodilation

The development of bronchial hyperreactivity in the setting of an acute viral illness in patients on propranolol has necessitated temporary discontinuation of therapy

Hyperkalemia

The cause of the hyperkalemia is not known, but the authors postulate that it was tumor lysis from the large ulcerated IH combined with impaired potassium uptake into cells as the result of b blockade

Inpatient VS. Outpatient

some centers hospitalize all children for initiation of treatment, whereas others do so only rarely

Some experts recommend intensive outpatient monitoring of patients, whereas others do little to no monitoring

Oral propranolol appears to have a favorable safety profile in children. Deaths or acute heart failure have been associated with propranolol initiation only in the settings of intravenous administration or drug overdose

Inpatient

Infants <8 weeks of gestationally corrected age any age infant with inadequate social support any age infant with comorbid conditions affecting the

cardiovascular system, the respiratory system including symptomatic airway hemangiomas or blood glucose maintenance

Outpatient

infants and toddlers older than 8 weeks of gestationally corrected age

Adequate social support without significant comorbid conditions

Cardiovascular Monitoring

Patients should be monitored with HR and BP measurement at baseline at 1 and 2 hours after receiving the initial dose after significant dose increase (>0.5 mg/kg/day) If HR and BP are abnormal the child should be monitored until the vitals normalize dose

response is usually most dramatic after the first dose; therefore, there is no need to repeat cardiovascular monitoring

multiple times for the same dose unless the child is very young or has comorbid conditions affecting the cardiovascular system or the respiratory system including symptomatic airway hemangiomas

HR vs. BP

Bradycardia is important to recognize because the accurate measurement of BP in infants may be challenging.

HR is simple to measure, and normative data for inappropriate bradycardia have been established as follows:

1. Newborns (<1 month old), <70 beats per minute2. Infants (1–12 months old), <80 beats per minute3. Children (>12 months old), <70 beats per minute Systolic BP varies significantly between1 month and 6 months of

age,so normative data are difficult to interpret

BP

Newborn:<57 mm Hg (<5th percentile oscillometric) or 64 mm Hg (2 SD auscultation)

6 months:<85 mm Hg (<5th percentile oscillometric) or 65 mm Hg (2 SD auscultation)

1year:<88 mm Hg (<5th percentile oscillometric) or 66 mm Hg (2 SD auscultation)

Ongoing Monitoring

As discussed earlier, patients should be monitored with HR and BP measurement at baseline and at 1 and 2 hours after a significant dose increase (>0.5 mg/kg/day), including at least 1 set of measurements after the target dose has been achieved

Most centers represented at the conference do not perform or recommend Holter monitoring in this setting on a routine basis

routine screening of serum glucose is not indicated. Propranolol should be administered during the daytime hours

with a feeding shortly after administration. Parents should be instructed to ensure that their child is fed regularly and to avoid prolonged fasts

Subglottic

Treatment includes such varied options: Observation (tracheotomy, and waiting for involution) medical management endoscopic techniques (laser, microdebrider, steroid injection) open excision propranolol therapy has dramatically changed the concepts  and

management of airway HOI, and as the application of this medication becomes more widespread

Smaller lesions that are relatively asymptomatic may be observed or treated medically with propranolol or oral steroids.

Symptomatic lesions are often treated with both propranolol and steroids, if not endoscopic laser treatment – surgery for larger lesions

Propranolol Use in PHACESyndrome

Theoretically, propranolol may increase the risk of stroke in PHACE syndrome patients by dropping BP and at tenuating flow through absent, occluded, narrow, or stenotic Vessels

Cardiac and aortic arch anomalies are also commonly seen in PHACE syndrome and require echocardiography to assess intracardiac anatomy and function.

Propranolol administration in these patients should be managed in close consultation with cardiology

The potential benefits of treatment must be weighed against the risks. The safe use of propranolol in individuals with PHACE has been

described in several small case reports and case series, although no clinical trials have been conducted to assess the overall safety

If the potential benefits of propranolol outweigh the risks, the consensus group recommends use of

1. the lowest possible dose,2. slow dosage titration upward, 3. Close observation including inpatient hospitalization in high-risk

infants, and 3 times daily dosing to minimize abrupt changes in systolic BP

Drug Interactions

THE ENDthanks for listeningDR.ALI MANSOUR