Refractory Hypoxemia in an Asymptomatic 6-Year-Old: It is not Always the Heart

Educational Objectives

• In patients with hypoxemia refractory to oxygen supplementation and normal cardiac anatomy, arteriovenous malformations must be considered, and prompt imaging should be performed to determine cause.

• Pulmonary arteriovenous malformations can have varied clinical presentation and require a thorough physical examination and diagnostic approach for management.

Case Report

Our patient was a 6-year-old female with no prior medical history who presented to her pediatrician’s clinic with left ear otalgia. She lived in Egypt with her parents with travel history to Europe and South America. Her vital signs were notable for hypoxia with saturation of 77% on room air, without clinical distress. On physical examination, she had clubbing of fingers, perioral and peripheral cyanosis, which parents had not noticed before. She was referred to the Emergency Department (ED) for further evaluation.

In the ED, she had minimal improvement in saturation to 80% with a nonrebreather mask. Her other vital signs were unremarkable: heart rate 107 beats per minute, respiratory rate 15 breaths per minute, blood pressure 110/72 mm Hg, and she was afebrile. Her laboratory work showed polycythemia with hemoglobin of 18.5 g/dL, white cell count 5.3 k/cm², and platelet count 350 k/cm². Her blood chemistry was unremarkable with normal renal and hepatic function. Methemoglobin levels were within the normal reference range. A chest radiograph obtained in the ED showed normal lung fields and cardiac border. She was then transferred to the Pediatric Intensive Care Unit (PICU) for management for hypoxemia, clubbing, and polycythemia of unclear cause.

Hospital Course

In the PICU, echocardiogram with bubble study showed normal cardiac anatomy and function including systemic and pulmonary venous connections. The bubble study was positive with complete opacification of the left atrium and left ventricle within 3 to 4 beats (Image 1). Given concern of an extra cardiac shunt, computed tomography (CT) angiography with contrast of chest, abdomen, and pelvis was performed. Imaging revealed a large left-sided pulmonary arteriovenous malformation (PAVM). Magnetic resonance imaging (MRI) brain to evaluate cerebral arteriovenous malformation (AVMs) was normal. Cardiac catheterization by pediatric Interventional Cardiology showed bilateral PAVMs. The PAVM in the left lobe was more extensive, supplied by branches of the left pulmonary artery. These PAVMs were causing a large right to left shunt with a Qp/Qs of 0.31.

Image 1.

Transthoracic echocardiogram demonstrating: (A) Apical 4 chamber prior to the injection of agitated saline contrast and (B) Complete opacification of left-side after 3 cardiac cycles following saline injection.

A multi-disciplinary discussion between cardiology, pediatric intensivist, and pulmonology explored treatment options given the size of the AVM and degree of the shunt. She underwent occlusion at four locations of the left PAVM. Amplatzer AVP2 device was used in three locations and a mechanically detachable plug was used for closure of another distal branch of the left PAVM (Image 2). Her oxygen saturations improved to 92% after closure of left PAVMs. Risks and benefits were considered, and given the improvement in saturations following closure of the left-sided PAVM, the decision was made to manage the right PAVM conservatively with close follow-up. Post catheterization, she continued to maintain normal saturations on room air. Clopidogrel 10 mg once daily for 3 months and aspirin 81 mg once daily long term were started for device prophylaxis. Cardiology and genetics follow-up were arranged and she was discharged home in stable condition.

Image 2.

Cardiac catheterization images demonstrating (A) large left-sided PAVM and (B) AVM after implantation of devices.

Discussion of Case and Literature

AVMs are pathogenic connections between a feeding artery and a draining vein. Pulmonary arteriovenous malformations occur in the pulmonary vasculature where segmental or subsegmental branches of the pulmonary artery form abnormal connections with the venous system. Arteriovenous malformations are pathogenic connections between a feeding artery and a draining vein. Pulmonary arteriovenous malformations occur in the pulmonary vasculature where segmental or subsegmental branches of the pulmonary artery form abnormal connections with the venous system. Arteriovenous malformations create a shunt that bypasses the pulmonary capillary bed which limits gas exchange. Pulmonary arteriovenous malformations are extremely rare with a prevalence estimated to be 38 per 100,000 individuals. Arteriovenous malformations create a shunt that bypasses the pulmonary capillary bed which limits gas exchange. Pulmonary arteriovenous malformations are extremely rare with a prevalence estimated to be 38 per 100,000 individuals. ¹ Most of the PAVMs occur in adulthood and only 10% occur in childhood. ² As in our case, PAVMs can be an incidental finding, or can present with symptoms such as hemoptysis, shortness of breath, or respiratory distress. Unilateral PAVMs are more common than bilateral PAVMs. Large and multiple PAVMs are more likely to be symptomatic. ² Despite large and bilateral PAVMs, our patient was asymptomatic with an incidental finding of hypoxemia. Pulmonary arteriovenous malformations require prompt recognition and treatment as they pose the risk of serious complications such as life-threatening hemorrhage, cerebral embolic stroke, and abscess. ³

The most common cause of pulmonary AVMs is Hereditary Hemorrhagic Telangiectasia (HHT) occurring in 40% to 60% of patients. ⁴ Hereditary Hemorrhagic Telangiectasia is caused by mutations in tumor growth factor (TGF)-β signaling pathway, which plays a role in angiogenesis. ⁵ While genetic testing is considered the gold standard for diagnosis, the Curaçao diagnostic criteria (epistaxis, telangiectasia, visceral lesions, and family history) also serves as a diagnostic tool with a positive predictive value of 100% and negative predictive value of 97.7% based off adult data.^6,7 However, the diagnostic accuracy of Curacao criteria is much lower in pediatric population;^8,9 therefore, our patient was referred to genetics for definitive workup of HHT.

Beyond hereditary causes and de novo mutations, PAVMs can also be sporadic or acquired secondary to other pathologies. One commonly recognized cause of acquired PAVMs is congenital heart disease. ¹⁰ There is case report of PAVMs developing in a pediatric patient with adrenocortical carcinoma. ¹¹ Although multiple theories for the pathogenesis of de novo AVMs have been reported, abnormal angiogenesis in response to pathogenic triggers such as hypoxia, infection or inflammation remains the underlying problem. ¹² Our patient had no identifiable triggers- there was no family history of AVMs, her birth history was unremarkable and there were no other physical examination findings suggestive of vascular abnormalities. Although our patient had no unifying diagnosis and genetic work-up was still pending as patient returned to Egypt, having an underlying diagnosis does not change management for PAVMs. To our knowledge, there are not many similar reported cases.

There was a strong suspicion of either a cardiac or intrapulmonary shunt since the patient’s hypoxemia was refractory to high levels of inspired oxygen on arrival to the PICU. The gold standard for diagnosing PAVMs remains CT angiography, not only for diagnostic purposes but for localizing the site of the PAVM and characterization of PAVMs. However, the utility of a transthoracic echocardiogram with agitated saline cannot be underestimated as a bedside modality. Using the bubble study, echocardiography functions as a minimally invasive procedure that has a diagnostic sensitivity of 97% and a negative predictive value of 99%. With intrapulmonary shunts, the agitated saline will be significantly delayed compared to right to left atrial shunts. ¹³ In our study there was a 3 to 4 heartbeat delay of left atrial opacification. Hypoxemia refractory to supplemental oxygen combined with a positive bubble echocardiography with delayed opacification was indicative of an intrapulmonary shunt. The CT chest was helpful in devising interventional strategies.

Embolization is considered the mainstay of treatment for PAVMs with a success rate of around 85% from adult data. ¹⁴ Most commonly used interventions for embolization are coils, microvascular plugs and Amplatzer vascular plugs with variations in the risk of AVM persistence after embolization. ¹⁵ Although our patient was noted to have 2 PAVMs, one on each side, only the more predominant PAVM was embolized. Embolization of the left PAVM resulted in an adequate response of her saturations to >92%. Right PAVM embolization would not have offered additional clear benefits such as increased oxygenation but could increase the risk of recanalization and the development of additional systemic collaterals. ¹⁶

Although largely safe, periprocedural complications include air embolus, thrombophlebitis, paradoxical embolization of mechanical devices, and pleuritic chest pain.^17,18 After embolization, close follow-up is indicated as the untreated right PAVM can proliferate and embolized AVMs carry a small risk of recanalization. ¹⁹ Generally, repeat imaging is recommended within 6 to 12 months of primary procedure, unless symptoms arise sooner. ¹⁸ Following the procedure, the patient’s family was counseled in depth on the importance of close monitoring of the right sided AVM which may require future intervention.

Final Diagnosis: Our case describes a patient with a large, extensive pulmonary AVM.

Conclusion

Hypoxemia and clubbing in otherwise healthy children have a broad differential diagnosis and require a thorough work-up. Hypoxemia unresponsive to supplemental oxygen is strongly suggestive of shunting. Pulmonary arteriovenous malformation, though less common than intra-cardiac shunts, can present in a similar fashion and physicians must have a high index of suspicion when evaluating patients with hypoxemia refractory to oxygen therapy. Echocardiography with bubble study is a helpful bedside tool that provides rapid diagnosis. Computed tomography angiography and catheterization provides definitive diagnosis. The management of PAVMs is similar irrespective of cause, with the primary modality considered embolization. Patients must be followed closely after embolization to monitor sequelae and observe for recurrence.

Author Contributions

All authors were involved in conception and design. Aymen Mirza drafted the initial manuscript. Bibek Bista, Vidhya Annavajjhala, and Chinyere O’Connor critically revised the manuscript and gave final approval.