AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Pulmonary arteriovenous malformations (PAVMs) were first described in 1897. They consist of abnormal communications between the pulmonary arteries and the pulmonary veins and are usually congenital in origin. However, they may also occur in a variety of acquired conditions, such as hepatic cirrhosis, schistosomiasis, mitral stenosis, trauma, actinomycosis, and metastatic thyroid carcinoma. In chronic inflammatory conditions (eg, bronchiectasis), communications between the bronchial arteries and the pulmonary arteries can also develop.

Hereditary hemorrhagic telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder. The clinical manifestations are secondary to growth of vascular malformations in a variety of organs, most commonly the skin, nasopharynx, gastrointestinal tract, lungs, and brain. HHT is generally recognized as a triad of cutaneous telangiectasia, recurrent epistaxis, and a family history of this disorder.

HHT has a wide distribution, although regional variations occur, and the overall frequency may vary from 1 case in 39,216 persons to 1 case in 2351 persons in some regions of France.

Approximately 70% of PAVM cases are associated with HHT. Conversely, approximately 15-35% of persons with HHT have PAVM. Arteriovenous malformations (AVMs) and HHT are congenital but usually do not clinically manifest until adulthood.

Historical perspectives

In 1896, Henry Jules Rendu published a case describing a 52-year-old man with telangiectasia and epistaxis in the French literature. In the Johns Hopkins Hospital bulletin in 1901, Sir William Osler reported on a family known to have hereditary telangiectasia and hemorrhage. Frederick Weber published subsequent descriptions of this disorder in a 1907 issue of the Lancet. That is how this disease received the name Rendu-Osler-Weber syndrome.

Definition

Telangiectasia and AVMs are the 2 abnormal vascular structures that occur in HHT. Telangiectasia is localized convoluted enlargement of the postcapillary venules. The walls of telangiectasia have smooth muscle proliferation, and perivascular lymphocytic infiltration is present. AVMs are much larger lesions than those of telangiectasia, consisting of direct connections of the pulmonary artery to the pulmonary vein. In AVMs, dilatation of the feeding vessel, and localized aneurysmal enlargement are present. Proximally, the vein may be septate and its walls smooth.

Anatomy

Approximately 53-70% of PAVMs are found in the lower lobes. Approximately 70% of patients have unilateral disease, 36% have multiple lesions, and 50% of those with multiple lesions have bilateral disease. PAVMs may be microscopic (ie, telangiectasis), but they are typically 1-5 cm. Occasionally, PAVMs as large as 10 cm are encountered. Approximately 10% of patients may have diffuse microvascular PAVMs in combination with larger, radiographically visible PAVMs.

The vascular channels are thin walled and lined with a layer of endothelium. The connective tissue stroma is scant and has no communication with the surrounding lung. Most PAVMs drain into the left atrium, but anomalous drainage to the inferior vena cava or innominate veins has been reported. The malformations may appear as one of the following: a large single sac, a plexiform mass of dilated vascular channels, or a dilated tortuous direct communication between artery and vein.

Anatomy of subtypes

PAVMs can be classified as simple or complex types on the basis of their architecture. Simple PAVMs have a single feeding segmental artery leading to single draining pulmonary vein. Approximately 79% of PAVMs are of the simple type (White, 1988); most of the associated aneurysms are nonseptate and occur in the lower lobes. Approximately 21% of PAVMs are complex, having 2 or more feeding arteries or draining veins. They often occur in the lingula and right middle lobe distributions.

Pathophysiology

Advances in the genetics of HHT have led to the recognition of the possible etiology of PAVM (McAllister, 1994; Porteus, 1989). Although primarily described in patients with HHT, these genetic abnormalities may also be present in patients without HHT. Genetic mapping in the last few years led to the discovery that HHT can be categorized into 2 linkage groups: HHT1 has been linked to band 9q33, and HHT2 has been linked to band 12q13. A third and rare variant of HHT not linked to chromosome 9 or 12 has been reported; its major manifestation is hepatic involvement.

Also, a third locus for HHT has been reported at band 3p22, where transforming growth factor (TGF)–b2 receptor gene is located. The HHT1 gene is associated with higher incidence of PAVM, epistaxis, mucocutaneous telangiectasia, and cerebrovascular malformations.

The genetic mutations at the 2 major loci are recognized. Endoglin is identified as the gene product for HHT1 on band 9q33 (Heutink, 1994). The endoglin, a TGFb, is a 180-kD glycoprotein that has been established to be a receptor for TGF-b1 and TGF-b2.

Approximately 16 mutations of the endoglin gene are reported. The mechanisms for gene mutation causing HHT1 include a dominant negative effect; a 2-hit model; and most likely, haploinsufficiency. The second locus for HHT has been mapped to chromosome arm 12q. The mutation in 12q may be in the b-glycan gene or in activin receptorlike kinase 1 (ALK-1). The ALK-1 protein has the properties of a type I serine-threonine kinase receptor. ALK-1 can bind either activin or TGFb in the presence of their respective type II receptors (Johnson, 1996). At least 12 mutations of the ALK-1 gene have been identified. The mechanisms of mutation appear to be similar to HHT1 mutations and include the dominant negative mechanism, the 2-hit model, and haploinsufficiency. The HHT2 gene is not predominantly associated with PAVM and cerebral AVMs.

Endoglin and ALK-1 bind TGFb, which is implicated in angiogenesis. PAVM likely develops as a result of interplay of various factors among diverse cells and matrix during vascular insults. Changes in endoglin and activin receptorlike kinase (ALK) might cause endothelial cells to respond abnormally to TGFb during the process of vascular remodeling, resulting in the formation of AVM.

Pathogenesis

The exact pathogeneses of PAVM is unknown. In the terminal arterial loops, a defect that allows dilatation of the thin-walled capillary sacs may occur. Alternatively, PAVMs are the result of incomplete resorption of the vascular septa that separate the arterial and venous plexus, which normally anastomose during fetal development. Some have also suggested that multiple small PAVMs develop as a result of capillary development failure during fetal growth. The large saccular PAVM develop by means of progressive dilation of the smaller plexus, leading to the formation of tortuous loops and multiloculated sacs. With time, the intervening vascular walls may rupture, resulting in the formation of a single large saccular PAVM.

Natural history

The natural history of PAVM has not been studied carefully. The initial manifestation of HHT is the appearance of cutaneous telangiectases or epistaxis. Fewer than 10% of patients who have visceral involvement by AVM have visceral signs and symptoms (eg, dyspnea or gastrointestinal bleeding) as the initial manifestation of HHT. The visceral manifestations occur in adults, reflecting the additional time needed for the enlargement of AVMs.

In one study of 16 patients, serial chest radiographs obtained over a median observation period of 18.9 years demonstrated enlargement in 4 patients and near total regression in 1 patient. The growth rate tended to be slow, with an increase of approximately 5-10 mm every 5-15 years.

Frequency

United States

In a 1953 study from The Johns Hopkins Hospital, 3 cases of PAVM were detected in 15,000 consecutive autopsies. The Mayo Clinic encountered 63 cases during the 20 years ending in 1972, and 38 cases were encountered during the subsequent 9 years ending in 1981. Approximately 70% of the cases of PAVM are associated with HHT, which is an autosomal dominant disorder. Conversely, approximately 15-35% of persons with HHT have PAVM.

To screen for occult brain, lung, and liver AVMs in pediatric patients with confirmed HHT, a study undertook molecular analysis and clinical assessment. The molecular analysis demonstrated the mutation-carrier status in 22 of 35 children. Nasal telangiectases were found in 68%, mucocutaneous telangiectases (fingers, lips, oral cavity) in 79%, PAVMs in 53%, hepatic arteriovenous malformations (HAVMs) in 47%, and cerebral arteriovenous malformations and/or cerebral ischemic changes secondary to PAVMs in 12% (Giordano, 2006).

Mortality/Morbidity

The mortality rate of PAVM has been 0-55%. Investigators in more recent studies have reported a mortality rate 0-15%; however, the duration of follow-up in these studies is short. The morbidity rate of untreated PAVM is also significant. The incidence of stroke is 11.4%, and the incidence of brain abscess is 6.8%. The total morbidity and mortality rate is 23%.

Sex

PAVM occurs twice as often in women than in men, but a male predominance exists among newborns.

Age

Approximately 10% of the cases of PAVM are identified in infancy or childhood; however, the incidence gradually increases through the fifth and sixth decades of life.

CLINICAL

Section 3 of 11  

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• Follow-up
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History

Symptoms in early life may vary from being totally absent to being severe. Common signs and symptoms are cyanosis, congestive heart failure, and fulminant respiratory failure. Symptoms related to PAVM often develop between the fourth and fifth decades of life. Symptoms are more common in persons with PAVM and HHT than in those with PAVM but not HHT.

• The most common complaint in symptomatic patients with PAVM is epistaxis caused by mucosal telangiectases.
• Dyspnea is the second most common complaint in patients with PAVM. Dyspnea is common in persons with large or multiple PAVMs and is observed in all patients who have clubbing. Some patients also have platypnea, which indicates an improvement in dyspnea upon reclining.
• Hemoptysis is the third most common symptom; massive hemoptysis may also occur. Bleeding from telangiectasis on the skin and in the gastrointestinal tract is observed in patients with PAVM and HHT. The incidence is 15-30%.
• The incidence of gastrointestinal hemorrhage in patients with HHT is 15-30%; specific incidences in patients with PAVM have not been reported.
• Less common complaints include chest pain, cough, migraine headaches, tinnitus, dizziness, dysarthria, syncope, vertigo, and diplopia. The cause of these symptoms is not entirely clear, but it may be related to hypoxemia, polycythemia, or cerebral vascular complications.

Physical

Superficial telangiectases attributable to HHT are the most common physical findings in patients with PAVM. These lesions are papular, slightly rounded, and sharply demarcated from surrounding skin. They have a few dendritic projections that are ruby colored and partially blanche with pressure. The lesions are present on the face, mouth, chest, and upper extremities (see Image 1).

• Murmurs or bruits over the location of the PAVM are heard in one half of patients. These murmurs are most audible during inspiration and are called machinery murmurs.
• Digital clubbing and cyanosis is also observed.
• The murmurs are loud during inspiration and increase when the patient assumes positions in which PAVMs are gravitationally dependent.
• Digital clubbing and cyanosis are observed in 60-80% of patients.
• The triad of dyspnea, cyanosis, and clubbing is uncommon and observed in a minority of patients.

Causes

• Epidemiology: Great heterogeneity of symptoms is noted among different families and within single large families with HHT. Some families with HHT predominantly have the PAVM and cerebral AVMs; whereas other affected families predominantly have GI mucosal telangiectasis, which lead to gastrointestinal bleeding and iron deficiency anemia.
• Inheritance: HHT is an autosomal dominant disorder; however, 20% of cases involve no family history of telangiectasia or recurrent bleeding. Penetrance is age related and nearly complete by age 40 years. Although the AVM in HHT are inherited and should be present at birth, they commonly manifest clinically during adult life, after the vessels have been subjected to pressure for several decades.
• Associated syndromes: Communication between pulmonary arteries and pulmonary veins has been reported in cases of trauma and in hepatic cirrhosis, schistosomiasis, mitral stenosis, actinomycosis, Fanconi syndrome, and metastatic thyroid carcinoma. Communications between bronchial arteries and pulmonary arteries that cause a left-to-right shunt develop in chronic inflammatory conditions such as bronchiectasis. Most individuals with PAVM have HHT. The diagnostic criteria for a definite diagnosis of HHT include at least 3 of the following:
  • Recurrent and spontaneous epistaxis
  • Multiple mucocutaneous telangiectases
  • Visceral lesions (eg, gastrointestinal AVM, PAVM)
  • First-degree relative with HHT by these criteria
• Associated noncardiac conditions: The most frequently reported associated noncardiac conditions are CNS complications, which occur in 30% of patients. Strokes occur in 18% of patients with CNS complications; transient ischemic attacks, in 37%; brain abscesses, in 9%; migraine headaches, in 43%; and seizures, in 8%. Paradoxic embolism across PAVM is the most likely mechanism for major noninfectious strokes. Embolism of infected material accounts for solitary or recurrent brain abscesses. These complications most commonly occur when the feeding arteries are larger than 3 mm in diameter. Hemoptysis and hemothorax are other potentially life-threatening complications. Hemoptysis occurs from ruptured PAVM or endobronchial telangiectasia.
• Other causes of PAVM
• • Idiopathic congenital PAVM: Idiopathic congenital PAVMs are likely to be single. They are less likely to become enlarged, and the are associated with fewer physical findings than other PAVMs. Idiopathic PAVM is diagnosed by using the same criteria as for other PAVMs. Idiopathic congenital PAVMs are successfully treated with embolotherapy.
  • Acquired AVMs in hepatopulmonary syndrome
    • Hepatopulmonary syndrome (HPS), increased alveolar-arterial oxygen gradient, and intrapulmonary right-to-left shunting (defined as the triad of liver disease) may occur in as many as 47% of patients with end-stage liver disease. All types of chronic liver disease may give rise to this syndrome. Approximately 80% of affected patients have signs and symptoms of end-stage liver disease before symptoms from PAVMs develop. These patients have dyspnea, platypnea, clubbing, cyanosis, hypoxia, and orthodeoxia. Pulmonary function results indicate normal lung volumes and expiratory flow rates with low diffusing capacity.
    • In contrasts to patients with HHT, patients with HPS rarely have discrete AVMs on chest radiographs. The calculation of the shunt fraction with the use of 100% oxygen, contrast echocardiography, and radionuclide scanning are diagnostic tests for HPS.
    • Results of HPS management have been disappointing. Liver transplantation may result in the resolution of HPS, and HPS is not a contraindication to liver transplantation. An improvement in HPS-related pulmonary shunting after therapeutic transjugular intrahepatic portosystemic shunting has been described.
  • Acquired AVMs after surgery for congenital cyanotic heart disease: PAVMs may develop after Glenn or modified Fontan procedures for congenital cyanotic heart disease. PAVMs are a known late complication of Glenn anastomosis (ie, superior vena cava [SVC] to right pulmonary artery [RPA]), which occur in as many as 25% of cases. The Fontan operation (ie, SVC to right atrium and proximal RPA; hepatic veins to left pulmonary artery) was designed as a surgical repair for congenital tricuspid atresia. Contrast echocardiography and radionuclide shunt studies have been used to diagnose PAVMs, and embolotherapy has been used successfully to occlude the PAVM in these cases.

DIFFERENTIALS

Section 4 of 11  

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Other Problems to be Considered

Consider the diagnosis of PAVM in individuals with any of the following presentations: (1) 1 or more pulmonary nodules associated with typical chest radiographic findings of PAVM; (2) mucocutaneous telangiectases; (3) unexpected findings such as dyspnea, hemoptysis, hypoxemia, polycythemia, clubbing, cyanosis, cerebral embolism, or brain abscess.

WORKUP

Section 5 of 11  

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• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Patients may have anemia because of the ongoing blood loss caused by AVMs in the gastrointestinal tract.
• However, hypoxemic patients without GI bleeding is usually present with polycythemia.

Imaging Studies

• Chest radiography (see Images 2-3, Images 7-8)
• • Chest radiographs reveal some abnormality in approximately 98% of patients. The classic abnormal radiographic finding is a round or oval mass of uniform opacity. The mass is frequently lobulated and most commonly appears in the lower lobes. A chest radiograph can reveal features that may be undetectable on plain chest radiographs; examples include a feeding vessel, an artery radiating from the hilus, and the vein deviating toward the left atrium.
  • In a patient who has clinical features suggestive of PAVM but normal chest radiographic findings, further evaluation with other modalities should be performed. Patients with microscopic PAVM may have normal chest radiographic findings. PAVM should also be considered in the differential diagnosis of a pulmonary nodule. A cautious approach to these patients is suggested before diagnostic needle biopsy is undertaken.
• Contrast-enhanced CT scanning (Image 4-5, Images 9-12)
• • The presence of PAVM and its vascular anatomy can also be evaluated by means of contrast-enhanced ultra-fast CT. CT allows for the detection of 90% of PAVMs, whereas, in one study, angiography allowed for the detection of only 60% of PAVMs. The superior sensitivity of CT is attributed to the absence of superimposition of lesions on CT views.
  • Three-dimensional (3D) helical CT scanning produces images of vascular structures that are continuously reconstructed by a helical CT scanner. The accuracy of 3D helical CT scanning is reported to be 95%.
• Tests for confirmation of an intrapulmonary right-to-left shunt
• • These tests should be performed initially. The shunt is best calculated by using the 100% oxygen method. Contrast echocardiography and radionuclide scanning have nearly 100% sensitivity and are used to confirm clinically significant PAVM. However, the 100% oxygen method for shunt calculation is the least expensive and readily available.
  • In patients who have a shunt fraction of more than 5%, as determined with the 100% oxygen method, further assessment and management is recommended. In some patients with a shunt fraction of less than 5% but a high clinical suspicion for PAVM, additional evaluation with contrast echocardiography or radionuclide scanning is recommended.
• Contrast echocardiography
• • Contrast echocardiography is an excellent tool for evaluating cardiac or intrapulmonary shunts. This technique involves the injection of 5-10 mL of agitated saline into a peripheral vein while simultaneously imaging the right and left atria with 2-dimensional echocardiography. In patients without right-to-left shunting, contrast is rapidly visualized in the right atrium and then gradually dissipates. In patients with intracardiac shunts, contrast is visualized in the left heart chambers within 1 cardiac cycle, after its appearance in the right atrium. In patients with PAVM, contrast is visualized in the left atrium after a delay of 3-8 cardiac cycles. Contrast echocardiography is almost 100% sensitive in detecting clinically important PAVMs.
  • In one case series, PAVM were visible in 11 of 14 patients with positive contrast echocardiographic findings who underwent pulmonary angiography. Six had abnormal chest radiographic results, and 8 had an increased A-a gradient. Contrast echocardiography had 100% sensitivity in this study. The finding of an intrapulmonary shunt by means of contrast echocardiography warrants further evaluation with standard pulmonary angiography or contrast-enhanced CT scanning.
• Radionuclide perfusion lung scanning
• • Radionuclide perfusion lung scanning is also useful in the diagnosis of PAVM, particularly if contrast echocardiography is not available.
  • In patients without an intrapulmonary shunt, the peripheral intravenous injection of technetium 99m–labeled macroaggregated albumin results in the filtering of these particles by the lung capillaries. However, anatomic shunts with dilated pulmonary vascular channels allow these particles to pass through the lung, with subsequent filtering by the capillaries in the brain and kidneys.
• Pulmonary angiography (see Image 6)
• • Despite advances in noninvasive diagnostic techniques, contrast-enhanced pulmonary angiography remains the criterion standard in the diagnosis of PAVM. This test is usually necessary if embolotherapy is being considered. Perform pulmonary angiography in all lobes of the lungs to look for unsuspected PAVM.
  • Currently, digital subtraction angiography appears to be replacing conventional angiography. Whether CT or MRI can replace standard pulmonary angiography in the diagnosis of PAVM requires further comparative studies. Presently, CT and MRI are appropriate noninvasive modalities for the follow-up evaluation of patients with proven PAVM.
• Magnetic resonance (MR) imaging: MRI has been reported to be useful in the diagnosis of PAVM. Rapidly flowing blood results in an absent or minimal MR signal, a so-called flow void. However, a PAVM may be indistinguishable from an adjacent air-filled lung on MRI, a significant limitation in screening for small lesions. Therefore, spin-echo MRI has reduced sensitivity and specificity for detection of PAVM, compared with those of other techniques. Better results are obtained with phase-contrast cine sequences, and MR angiography can be used to define the vascular anatomy of a PAVM. A combination of MR techniques may be useful in differentiating PAVM from various other lesions, but more comparative data are required before the routine use of MRI is recommended.

Other Tests

• Pulmonary function tests: Oxygenation is commonly affected in individuals with PAVM. Most patients have saturation levels of less than 90% at rest. Orthodeoxia is a decrease in PaO₂ or SaO₂ that occurs when one assumes an upright position from the supine position. Patients with this finding have normal spirometric findings and a mildly reduced diffusing capacity. Recent case series have indicated that 80-100% of patients with PAVM have either a PaO₂ of less than 80 mm Hg or an SaO₂ of less than 98% on room air.
• Shunt fraction measurement: The shunt fraction is most accurately assessed by using the 100% oxygen method, which involves the measurement of PaO₂ and SaO₂ after the patient breathes 100% oxygen for 15-20 minutes. The fraction of cardiac output that shunts right-to-left circulation is elevated in patients with PAVM; normal values are less than 5%. A shunt fraction of more than 5%, as determined by using the 100% oxygen method, has a sensitivity of 87.5% and a specificity of 71.4%.
• Exercise testing: Patients with PAVM have reduced exercise tolerance. In most patients, incremental exercise testing results in decreased saturation. One case series of patients showed that the average maximum oxygen consumption was 61% of the predicted value; saturation decreased from 86% at rest to 73% with peak exercise.

Procedures

• Right heart catheterization
• • Most patients with PAVM have normal or low pulmonary arterial pressure. Despite severe oxygen desaturation, the mean pulmonary arterial pressure is low in most patients.
  • Their cardiac output is generally normal to moderately elevated.
  • Patients may develop new pulmonary hypertension or increased baseline pulmonary hypertension after embolization or resection of a large PAVM.
• The radionuclide method of shunt calculation is expensive and not routinely available at most hospitals; however, it has several advantages compared with the 100% oxygen method.
• • Arterial blood gas sampling is not needed.
  • The 100% oxygen method may overestimate intrapulmonary shunt.
  • The radionuclide method is more suitable for shunt measurement during exercise.

TREATMENT

Section 6 of 11  

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Medical Care

The role of hormonal therapy in patients with recurrent bleeding secondary to gastrointestinal or nasopharyngeal mucosa has been reported in the literature. Findings from these small studies have suggested a modest benefit. Anecdotal reports have also suggested successful treatment of epistaxis and gastrointestinal hemorrhage by using danazol, octreotide, desmopressin, and aminocaproic acid.

Definite therapy for PAVM involves therapeutic embolization or surgical resection.

• Catheter intervention - Therapeutic embolization
  • Embolization therapy (ie, embolotherapy) is a form of treatment based on occluding the feeding arteries to a PAVM.
  • The first successful case of embolotherapy of PAVM was reported in 1977 and involved the use of handmade steel coils. Since then, embolization with coils and/or detachable balloons has been reported in numerous series of more than 250 patients. Other embolic materials include polyvinyl alcohol, cotton wool coils, and stainless steel coils.
• Indications for embolotherapy
  • Progressive enlargement of the lesions
  • Paradoxic embolization
  • Symptomatic hypoxemic
  • Feeding vessels of 3 mm or larger
• Techniques
  • The technique of coil embolotherapy involves the localization of the PAVM by means of angiography, followed by selective catheterization of the feeding artery. A steel coil is advanced through the catheter and placed distal to any branch of the vessel. Sometimes, more than 1 coil is required to completely occlude the vessel. Multiple PAVMs can be embolized in a single session.
  • The second embolotherapeutic technique uses detachable balloons. After localization of a PAVM, a balloon catheter is exchanged over a guidewire and positioned at the neck of the PAVM.
• Results
  • Follow-up CT scans obtained 1 or more years after embolotherapy indicate that 96% of PAVMs are either undetectable or reduced in size. These findings occur secondary to thrombosis and retraction of the aneurysmal sac after successful vascular obstruction. In one series of 45 patients who underwent embolotherapy of large (>8 mm) PAVMs, 98% of the PAVMs were occluded during the initial attempt, 84% of patients remained successfully treated, and 16% of patients had persistent PAVMs (Lee, 1997). The persistence of the PAVMs was caused by recanalization of initial successful occlusion in 5 patients, and it was caused by interval growth of new feeding vessels in 3 patients. All 8 of the persistent PAVMs were successfully occluded during a second procedure, although 1 PAVM required a third procedure for permanent occlusion.
  • A summary of 10 published series of therapeutic embolization for PAVM documented an average success rate of 98.7%. Balloon embolotherapy is generally used in PAVM with a feeding vessel larger than 7-10 mm.
  • Embolotherapy appears to be the treatment of choice because major surgery, general anesthesia, and loss of pulmonary parenchyma may be avoided. Embolotherapy is a clear choice in patients with multiple or bilateral PAVMs or in patients who are poor surgical candidates.
• Postcatheterization care/precautions: Postcatheterization precautions include hemorrhage, vascular disruption after balloon dilation, pain, nausea and vomiting, and arterial or venous obstruction from thrombosis or spasm.
• Complications
• • Possible complications include rupture of blood vessels, tachyarrhythmias, bradyarrhythmias, and vascular occlusion.
  • Pleuritic chest pain is the most common complication, and it is observed in 12% of patients. This pain usually responds well to analgesics. Radiographic evidence of pulmonary infarction is observed in 3% of patients.
  • Air embolism during embolotherapy is suspected in 4.8% of patients; they developed transient symptoms such as angina, perioral paraesthesias, and bradycardia.
  • Device migration has been reported in 1.2% of embolization attempts.
  • Long-term follow-up evaluation has shown potentially serious complications in 2% of patients treated with embolotherapy.
  • Symptomatic recanalization was observed with 0.5% of procedures.
  • A new or increased pulmonary hypertension after embolization has been reported in several patients. Incidence of complication appears to be higher when the feeding vessels of more than 8 mm were occluded.

Surgical Care

Until 1977, surgery was the only method of treatment. Ligation, local excision, segmentectomy, lobectomy, or pneumonectomy was performed in most cases. The reported perioperative mortality rate from surgery varied from 0-9%. Postoperative follow-up evaluation shows recurrence or enlargement of the PAVM in as many as 12% of patients. Surgery is the best choice for patients with an untreatable allergy to the contrast material.

• Indications: Indications for surgery are progressive PAVM enlargement, paradoxic embolization, and symptomatic hypoxemia. The treatment of all PAVMs with feeding vessels 3 mm or larger is also recommended.
• Techniques: Standard thoracic surgical techniques, such as ligation of PAVM, local excision, segmentectomy, lobectomy, or pneumonectomy, have been performed. In some cases, staged bilateral thoracotomies are performed. Recently, video-assisted thoracoscopic resection of a small PAVM has been performed.
• Results: Postoperative follow-up evaluation shows recurrence or enlargement of another PAVM in as many as12% of patients. During a follow-up evaluation performed 8 years after surgery, one case of stroke and one case of mortality related to PAVM occurred. Reports also suggest the development of pulmonary arterial hypertension. Moderate surgical techniques for the resection of PAVM are associated with a negligible mortality rate, but they are associated with the morbidities that accompany a thoracotomy.
• Complications: According to various reported series, the perioperative mortality has varied from 0-9.1%. Most of the studies that reveal high mortality rates were reported before 1960. Postoperative morbidities have been well reported.
• Activity: Patients with PAVM have reduced exercise tolerance.
• Long-term clinical and imaging results of technically successful PAVM embolization in 150 patients were reviewed. Four hundred and fifteen PAVMs were occluded during 205 procedures. Complications included respiratory symptoms (n = 13), cerebral ischemia (n = 4), brain abscess (n = 5), hemoptysis (n = 3), and seizure (n = 1). Imaging showed PAVM involution in 97% of embolized lesions and 11 residual lesions (2.8%) in 10 patients (6.9%). The other 97 previously small pulmonary AVMs had enlarged to a significant size in 28 patients (18%). These data emphasize ongoing clinical and anatomic evaluation after PAVM embolization (Pollak, 2006).
• Large pulmonary arteriovenous fistulas (PAVFs) present significant difficulty for transcatheter treatment. However, initial experience with Amplatzer duct occluder (ADO) looks promising. One case series reported 5 patients, aged 3-73 years, with large PAVFs who underwent successful transcatheter closure with ADO. No complications occurred and the patients' arterial oxygen saturation and exercise tolerance improved. Thus, transcatheter closure of large PAVFs with the ADO is effective and can eliminate the need for surgical intervention. The newly designed Amplatzer vascular plug is undergoing clinical trials (Bialkowski, 2005).

MEDICATION

Section 7 of 11  

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Drug therapy is not currently a component of the standard of care for this condition.

Patients with PAVM should be given antibiotic prophylaxis before dental and surgical procedures to prevent seeding of the PAVM and the subsequent development of a cerebral abscess.

Drug Category: Antibiotics, prophylactic

Antibiotic prophylaxis is given to patients before performing procedures that may cause bacteremia.

FOLLOW-UP

Section 8 of 11  

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Deterrence/Prevention

• See Medication for the recommended prophylactic regimen for dental, oral, sinus, and genitourinary and gastrointestinal procedures.
• • Amoxicillin 3 g orally (PO) 1 hour or 2 g intravenously (IV) 30 minutes before the procedure, followed by 1.5 g PO/IV hours after the initial dose
  • For patients who are allergic to penicillin, erythromycin 1000 mg PO 2 hours before the procedure, followed by 500 mg PO 6 hours after the initial dose
  • For patients who are allergic to penicillin, clindamycin 300 mg PO 1 hour or 300 mg IV 30 minutes before procedure, followed by 150 mg PO/IV 6 hours after initial dose
• The recommended prophylactic regimen for genitourinary and gastrointestinal procedures includes 1 of the following:
• • Amoxicillin 3 g PO 1 hour before the procedure, followed by 1.5 g PO 6 hours after the initial dose, plus gentamicin 1.5 mg/kg IV 1 hour before the procedure; this may be repeated 8 hours after the initial dose.
  • For patients who are allergic to penicillin, vancomycin 1 g IV over 1 hour plus gentamicin 1.5 mg/kg IV 1 hour before the procedure; this may be repeated 8 hours after the initial dose.

Complications

• Seizure
• Migraine headaches
• Transient ischemic attack
• Cerebral vascular accident
• Brain abscess
• Hypoxemia, orthodeoxia
• Hemothorax
• Life-threatening hemoptysis
• Pulmonary hypertension
• Congestive heart failure
• Polycythemia
• Anemia
• Infectious endocarditis

Patient Education

• Thoroughly educate patients with PAVM and patients with HHT about their diagnosis and its clinical implications, complications, and hereditary nature.

MISCELLANEOUS

Section 9 of 11  

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• Introduction
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• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Percutaneous needle biopsy of a solitary pulmonary nodule may lead to catastrophic pulmonary hemorrhage because of PAVM; therefore, consider PAVM in the differential diagnosis of a pulmonary nodule and rule out PAVM before performing needle biopsy.
• Obtain a chest radiograph to rule out PAVM in patients presenting with a brain abscess.
• The family members of patients with HHT or PAVM should be screened with the methods described in Special Concerns below.
• In all patients, consider intrapulmonary shunts as causes of hypoxemia because of PAVM.

Special Concerns

• Screening of family members with PAVM or HHT may be helpful.
• • Family members of patients with HHT should be routinely screened for possible PAVM.
  • The incidence of PAVM is approximately 15-20% in unselected patients with HHT.
  • Screening families with HHT is particularly important when PAVM has already been diagnosed in at least one relative.
  • The incidence of PAVM is approximately 35% among relatives of persons HHT.
• Evaluate all patients by obtaining a history and by performing a focused physical examination, chest radiography, and a 100% oxygen shunt study.
• • Patients with an increased shunt fraction may be referred for contrast CT scanning or pulmonary angiography, whereas patients with abnormal chest radiographic findings combined with a shunt fraction in the reference range are referred for contrast echocardiography, followed by angiography if the echocardiographic findings are normal.
  • Routine screening of family members with CT or contrast echocardiography is expensive, and pulse oximetry is insensitive as a screening tool.
  • Routine genetic screening of family members of patients with HHT is likely to play an increasingly important role in the future. The current screening methods for endoglin mutations and mutations in the active ALK-1 gene are useful in to detecting responsible mutations in 75-100% of families with HHT. Once the genetic defect is identified for a given family with HHT, genetic screening is 100% sensitive and specific in determining the presence of clinical HHT in individual family members. Therefore, in families with a known genetic defect, genetic screening of all family members by analyzing their peripheral blood is recommended.
• Pregnancy
• • The risks in pregnant women with HHT and PAVM are significant, and knowledge of these risks is important in counseling of affected individuals and families.
  • In one series, maternal complications occurred in almost half of pregnancies involving patients with PAVM. In pregnant women with PAVM, worsening of right-to-left shunt, fatal pulmonary hemorrhage, and stroke occurred. Progression of vascular malformations in the cerebral, pulmonary, and hepatic circulation during pregnancy has also been documented. Therefore, all women with HHT or a family history of HHT who are considering pregnancy should be screened for PAVMs.
• Acquired PAVM after surgery for congenital cyanotic heart disease
• • The Glenn procedure is SVC-to-RPA (end-to-end) anastomosis; this has been used to bypass tricuspid atresia in congenital heart diseases. The Fontan procedure creates a communication from the right atrium to the pulmonary artery, and one of its early modifications interposes a communication from the right atrium to the right ventricle. Both of these procedures are associated with the development of intrapulmonary shunting via the PAVMs approximately 6-10 years after the repair procedure. Although microscopic pulmonary-to-systemic arterial shunting is observed in most patients, important PAVM confirmed by 2-dimensional echocardiographic contrast study has been reported in 25% of the patients (McFaul, 1977; Cloutier, 1985). The currently popular hemi-Fontan (side-to-side SVC-to-RPA anastomosis) operation and, to a lesser extent, the fenestrated lateral tunnel Fontan operation are also associated with the development of PAVMs.
  • The mechanism of PAVM is hypothesized to be multifactorial and involves low pulsatile pulmonary blood flow, predominant perfusion to the lower lobes, and diminished flow to the upper and middle lobes exacerbated by gravitational effects. Hypoxemia and hemoconcentration may be other factors contributing to the formation of PAVM.
  • The development of PAVMs is clinically suspected when cyanosis, hypoxemia, and dyspnea return. The presence of PAVMs is confirmed by means of radionuclide scanning or 2-dimensional echocardiographic contrast study. To determine the hemodynamic significance of PAVMs and to identify their exact locations, further evaluation by means of cardiac catheterization and pulmonary angiography may be undertaken (Laks, 1979).
  • Treatment of a significant PAVM includes therapeutic embolization or ligation of venous collaterals and operative reconstruction. Percutaneous transcatheter embolization is the least invasive technique and generally consists of embolization with coils or balloons. The procedure may be repeated at a later date if a significant shunt still persists. The adverse effects of embolization are pulmonary infarction, chest pain, fever, and pleural effusions. Reconstruction of SVC-to–right atrium continuity and RPA ligation have been suggested. Reimplantation of the pulmonary veins of the right lower lobe to the right atrium has also been recommended. These procedures may be associated with significant morbidity or mortality rates (Gomes, 1984).

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Mucosal telangiectasias are shown in a patient with hereditary hemorrhagic telangiectasia (HHT).
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Media file 2:  Left lower lobe arteriovenous malformation (AVM).
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Media file 3:  Lateral radiograph showing a left lower lobe arteriovenous malformation (AVM).
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Media file 4:  Large left lower lobe arteriovenous malformation (AVM) showing a feeding vessel to the left atrium.
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Media file 5:  Another view of the infused CT scan of the left lower lobe arteriovenous malformation (AVM) shown in Image 4.
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Media file 6:  Pulmonary angiographic findings are required not only to confirm the diagnosis but also to plan therapeutic embolization.
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Media file 7:  Small arteriovenous malformations (AVMs) in the right and left lower lobes.
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Media file 8:  Lateral radiograph shows a left lower lobe arteriovenous malformation (AVM).
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Media file 9:  Contrast-enhanced CT scan showing a left lower lobe arteriovenous malformation (AVM).
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Media file 10:  Right lower lobe arteriovenous malformation (AVM).
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Media file 11:  CT scan obtained after coil embolotherapy.
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Media file 12:  Left lower lobe embolotherapy performed at the same sitting as the coil embolotherapy depicted in Image 11.
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Media type:  CT

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

• Allen SW, Whitfield JM, Clarke DR, et al. Pulmonary arteriovenous malformation in the newborn: a familial case. Pediatr Cardiol. Jan 1993;14(1):58-61. [Medline].
• Beck A, Dagan T, Matitiau A, Bruckheimer E. Transcatheter closure of pulmonary arteriovenous malformations with Amplatzer devices. Catheter Cardiovasc Interv. Apr 30 2006;67(6):932-937. [Medline].
• Bialkowski J, Zabal C, Szkutnik M, et al. Percutaneous interventional closure of large pulmonary arteriovenous fistulas with the amplatzer duct occluder. Am J Cardiol. Jul 1 2005;96(1):127-9. [Medline].
• Borsellino A, Giorlandino C, Malena S, et al. Early neurologic complications of pulmonary arteriovenous malformation in a newborn: an indication for surgical resection. J Pediatr Surg. Feb 2006;41(2):453-5. [Medline].
• Chilvers ER, Whyte MK, Jackson JE, et al. Effect of percutaneous transcatheter embolization on pulmonary function, right-to-left shunt, and arterial oxygenation in patients with pulmonary arteriovenous malformations. Am Rev Respir Dis. Aug 1990;142(2):420-5. [Medline].
• Cloutier A, Ash JM, Smallhorn JF, et al. Abnormal distribution of pulmonary blood flow after the Glenn shunt or Fontan procedure: risk of development of arteriovenous fistulae. Circulation. Sep 1985;72(3):471-9. [Medline].
• Dutton JA, Jackson JE, Hughes JM, et al. Pulmonary arteriovenous malformations: results of treatment with coil embolization in 53 patients. AJR Am J Roentgenol. Nov 1995;165(5):1119-25. [Medline].
• Faughnan ME, Lui YW, Wirth JA, et al. Diffuse pulmonary arteriovenous malformations: characteristics and prognosis. Chest. Jan 2000;117(1):31-8. [Medline].
• Faughnan ME, Thabet A, Mei-Zahav M, et al. Pulmonary arteriovenous malformations in children: outcomes of transcatheter embolotherapy. J Pediatr. Dec 2004;145(6):826-31. [Medline].
• Ference BA, Shannon TM, White RI Jr, et al. Life-threatening pulmonary hemorrhage with pulmonary arteriovenous malformations and hereditary hemorrhagic telangiectasia. Chest. Nov 1994;106(5):1387-90. [Medline].
• Gallitelli M, Guastamacchia E, Resta F, et al. Pulmonary Arteriovenous Malformations, Hereditary Hemorrhagic Telangiectasia, and Brain Abscess. Respiration. Jul 21 2005;[Medline].
• Giordano P, Nigro A, Lenato GM, et al. Screening for children from families with Rendu-Osler-Weber disease: from geneticist to clinician. J Thromb Haemost. Jun 2006;4(6):1237-45. [Medline].
• Gomes AS, Benson L, George B, Laks H. Management of pulmonary arteriovenous fistulas after superior vena cava- right pulmonary artery (Glenn) anastomosis. J Thorac Cardiovasc Surg. Apr 1984;87(4):636-9. [Medline].
• Gossage JR, Kanj G. Pulmonary arteriovenous malformations. A state of the art review. Am J Respir Crit Care Med. Aug 1998;158(2):643-61. [Medline].
• Heutink P, Haitjema T, Breedveld GJ, et al. Linkage of hereditary haemorrhagic telangiectasia to chromosome 9q34 and evidence for locus heterogeneity. J Med Genet. Dec 1994;31(12):933-6. [Medline].
• Johnson DW, Berg JN, Baldwin MA, et al. Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat Genet. Jun 1996;13(2):189-95. [Medline].
• Laks H, Kaiser GC, Mudd JG, et al. Revascularization of the right coronary artery. Am J Cardiol. Jun 1979;43(6):1109-13. [Medline].
• Laks H, Williams W, Trusler G, Castaneda A. Subclavian arterioplasty for the ipsilateral subclavian-to-pulmonary artery shunt. Circulation. Aug 1979;60(2 Pt 2):115-9. [Medline].
• Lenato GM, Guanti G. Hereditary Haemorrhagic Telangiectasia (HHT): genetic and molecu