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Many patients are born with lymphatic abnormalities or are susceptible to pathology following cardiac surgery. It therefore becomes important to evaluate and treat lymphatic disorders in centers performing congenital heart surgery. Programs can make strides towards starting a lymphatic branch if appropriately equipped with proper staff, tools, and other capabilities to perform lymphatic system access, imaging, and intervention. In reality, many of these components already exist in most centers, and a successful and comprehensive program can be established by enlisting these already established services.
Any institution can properly form a lymphatic program with the appropriate training, personnel, and equipment to provide treatment options for patients with lymphatic perfusion problems and congenital heart disease. The personnel and understanding of the pathophysiology are of the utmost importance and form the backbone of the program.
A lymphatic program can bolster any center that is offering surgery for congenital heart disease. Most of these centers come equipped with many of the same components that they would need to start a lymphatic program. Reutilization of these services and identifying the appropriate faculty is one of the earliest steps needed to form a lymphatic program. Ideally, the recruited team members should possess a strong understanding in lymphatic anatomy and physiology. Once recruited, it is pivotal to define roles in the program. This internal recruitment and defining of roles, along with an exceptional knowledge base, is quintessential as the foundation for any lymphatic program.
Programs without a lymphatic team can look towards centers such as UCLA's Congenital Lymphatic Imaging and Intervention Program or the Children's Hospital of Philadelphia's Mark and Jill Fishman Center for Lymphatic Disorders as examples of a well-formed lymphatic team. A well-constructed team, as seen in Figure 1, starts with a pediatric interventional cardiologist with possibly an interventional radiologist, cardiac surgeons, microvascular surgeons, cardiac MRI, and an imaging team. In addition, cardiac anesthesiology is preferred due to the length of these lymphatic cases, and an ICU team to assist in the care of these patients pre and postoperatively. As exemplified by the clinical cases in this manuscript, hematology-oncology physicians and pharmacists can assist in providing insight into managing certain MEK inhibitors and other novel modulatory therapy that some patients require. The use of these mitogen-activated protein kinase inhibitors in lymphatic patients with underlying genetic conditions has led to abrupt improvement and a remodel of the lymphatic system in patients.
Subspecialists from other fields such as pulmonology and gastroenterology play a role in treating patients with plastic bronchitis and protein losing enteropathy, respectively. The ideal program, as with all programs, would also include an ancillary staff team of clinical care coordinators and research coordinators to help oversee the intricate care these patients receive. Identifying deficiencies in any of these areas becomes an appropriate place to begin in constructing the backbone of a lymphatic program. Once all the appropriate, trained, and educated members are assembled, the process of actively imaging and treating can commence. The diagram below represents a schematic for a comprehensive lymphatic program. This can be simplified by identifying a champion who both understands the need and the process for intervening on these diseases, often a dedicated interventional radiologist or interventional pediatric cardiologist who can understand the anatomy and perform the initial imaging procedures and can lead building a better team.
Knowledgebase, understanding, and technique play a significant role in the operation of this team. Although the components to a successful lymphatic program may already be available at an institution, the training and comfort with beginning to care for lymphatic patients may not be present at first. To overcome this hurdle, it is important to both find a mentor, likely from an established program, and to work alongside said mentor to identify weaknesses and strengthen both techniques and understanding of procedures. Ideally, one may consider attending cases with and serving as an assist to their mentor while in the learning stages. In addition to a mentor, further practice can take place via simulation and utilization of the tools, techniques, and medication specific to lymphatic procedures.
The lymphatic system has many components with a variety of functions. The lymphatic system is a pivotal yet forgotten component of both the immune and circulatory system. It comprises of primary lymphatic organs such as the thymus and bone marrow, as well as secondary organs such as the spleen and lymph nodes. This organ functions to return excess lymphatic fluid and waste products to the bloodstream including protein and cellular debris. In addition, this organ also functions in immune surveillance and defense by assisting in leukocyte transportation from bone marrow to lymph nodes.
At a baseline prior to intervention, many patients have variable lymphatic anatomy, often resulting in abnormal lymphatic circulation. Pathologic anatomy results in connections to potential spaces for lymphatic leakage.
This can result in the clinical presentation of chylothorax, chylopericardium, chylous ascites, protein losing enteropathy, plastic bronchitis, anasarca, pulmonary lymphangiectasis, dermal lymphatic backflow, and so on. Pathology can present at any level from that of the ducts draining into the subclavian veins to that of the cisterna chyli which is a large midline collection of lymphatic vessels inferior of the diaphragm around the level of the thoracolumbar junction (T11-L1) that connects to the thoracic duct.
The exact cause of these malformations is often unclear. They can result from abnormalities in fetal development, a genetic mutation, or as part of syndromes including Noonan syndrome, Turner syndrome, Down syndrome, GLA and KLA.
They are often present in patients with congenital heart disease and can become clinically significant after surgical correction, most specifically with staged single ventricular palliation surgeries. The change in hemodynamics secondary to these CHD surgeries create a profound effect on the morphology and function of the lymphatic system.
With the resolution of one disease, and creation of another, it becomes imperative that any center performing congenital cardiac surgery can treat lymphatic flow disorders.
The first step in this process is often accessing the lymphatic system. This step is often the most time consuming, and often the most intimidating, amongst interventionalists performing these procedures, but the practitioner can be become proficient quite quickly as it utilizes the same image guided techniques used in other procedures. To comprehensively image the central lymphatic system, needle access must be achieved by bilateral inguinal lymph nodes, hepatic lymphatics, and mesenteric lymph nodes, as seen in Figure 3.
Once accessed, the next step in evaluating the lymphatic system involves a novel lymphatic MRI protocol. This is accomplished through dynamic contrast enhanced magnetic resonance lymphangiography (DCMRL) where the patient is placed in a magnetic resonance imaging (MRI) system and a gadolinium-based contrast agent is slowly hand injected into the lymph nodes, as described before. This allows for imaging of the central lymphatic system and provides both anatomical and physiological information regarding the lymphatic system such as in Figure 4.
Two sequences, time-resolved angiography with stochastic trajectories (TWIST) and contrast enhanced MRA for high quality 3D imaging, are the standard for functional and anatomic assessment of the lymphatic system. Figure 3 demonstrates a constructed lymphatic system made using these imaging modalities. MRI protocol and imaging parameters can be found outlined by Dori et al in the seminal paper describing this technique, “Novel Lymphatic Imaging Techniques,” Techniques in Vascular and Interventional Radiology, December 2016.
The clinical implications from just the ability to image alone can be limitless. For instance, a 6-month-old male who was status post coarctation repair presented with a complicated high volume left chylothorax. The patient underwent 2 weeks of nothing by mouth status and one week of octreotide treatment. His condition worsened with attempted treatment and lymphatic imaging was obtained revealing a leak in the thoracic duct, Figure 5.
In another case, there was a 7-year-old male with history of hypoplastic left heart syndrome palliated with a fenestrated Fontan who presented with plastic bronchitis and ultimately was listed for heart transplant. He was intubated and subject to numerous respiratory codes secondary to cast production. A DCMRL was performed and was found to have a leaking branch perfusing the right lung where the pulmonary team was consulted and aided in performing a bronchoscopy after percutaneous, transabdominal access to the thoracic duct was achieved. Blue dye (Isosulfan Blue) was injected proximal to his lesion and was seen perfusing his bronchi where active casts were forming, Figure 6. The vessel was selectively embolized using TRUFILL, a liquid embolic system created by Cordis Neurovascular, based in Miami Lakes, FL. Following his intervention, he was extubated on postoperative day 1. No further cast recurrence occurred. He continued to improve with normalization of his Fontan pressures and was removed from the transplant list.
Gastroenterologists also play an important role in these interventions. In this final case, a 14-year-old female with a failing Fontan was diagnosed with protein losing enteropathy, chylous ascites, and pleural effusions; a multicompartment disease. She underwent intrahepatic DCMRL, Figure 7, showing abnormal hepato-duodenal connections with contrast briskly filling the duodenum confirmed with concurrent colonoscopy (Fig. 8) by gastroenterology. These vessels can then be selectively targeted and embolized to help with symptoms. This disease, however, can require several interventions to eliminate these connections, and often require thoracic duct decompressive procedures as well.
The procedures performed require knowledge of interventional techniques, surrounding structures, and an understanding of how to use guide wires and microcatheters. These procedures therefore require a skilled interventional cardiologist or interventional radiologist. These specialists will then also need to become comfortable using agents such as TRUFILL and even lipiodol. Lipiodol was first synthesized in 1901 as an iodinated poppy seed oil. Over the course of over a century, it was originally developed as a therapeutic agent, became a contrast medium and return to therapeutic use, particularly in the field of lymphangiography and intervention.
It is often injected into the lymphatic vessels, as performed in traditional lymphangiography, which can directly embolize small leaking vessels through its sclerosing properties.
In addition to interventionalists, cardiac, and microvascular surgeons are essential when the thoracic duct is occluded and other treatment modalities are required. These include both lymphovenous bypass (LVB) and lymphovenous anastomosis (LVA).
In an LVB, an attempt is made to return lymphatic fluid to the venous system earlier along the pathway, often at the level of the left neck veins vein. Due to concerns of venous hypertension in larger caliber veins, attempts to bypass to venules resulted in lymphatic and venule anastomosis, the LVA, as demonstrated in Figure 9.
This procedure is often termed a “supermicrosurgery” as it involves surgical microscopic loops or cameras and techniques to anastomose often 1-2 mm vessels together. Through these, a patent lymphatic channel has a connection to a recipient venous vessel allowing outflow of lymphatic fluid and improvement of buildup.
When means of microsurgery are hindered, other corrective options exist such as stenting, further stressing the role of the interventionalist on the lymphatic team. Stenting provides a way to perform lymphovenous anastomoses when true surgical connections are unobtainable, whether it be secondary to technical limitations or otherwise.
Similar to the surgical counterpart, it allows for decompression of both antegrade and retrograde lymphatic flow, although long term patency of this approach is difficult to achieve due to thrombosis of the stent, requiring multiple re-interventions.
In review, any lymphatic program is only as strong as the sum of its many parts. These parts each play specific role in the functioning of the program with dedicated team members forming the backbone. When advising colleagues who are trying to establish a lymphatic program, the most important item of advisement is to spend the time discussing the physiology and getting the correct individuals on the team. It is only then that the team is creating an algorithmic approach to performing the assessment, imaging, and intervention. Of course, par the course for any budding program, there may be limitations to what can be done and there should be no hesitation to reach out and utilize the resources available in centers performing these procedures at a higher volume.
Creating a lymphatic program opens a world of opportunities for both institutions providing care, and the patients receiving that care. The capacity to manage and take care of patients with lymphatic disease is as essential to centers performing congenital cardiac surgery as having a catheterization program. Lymphatic disruption, or revealing lymphatic perfusion problems, are a common complication of cardiac surgery and the standard of care should be to effectively understand and be able to intervene in a real time manner. Much like the lymphatic interventions themselves, the beginning processes are tedious, meticulous, and demanding. Regardless, lymphatic programs in their infancy should focus on first achieving a deep understanding of the advances made in lymphatic imaging and intervention as well as pitfalls in the last 5 to 10 years and on a monthly basis. Second to this should be a focus on building a dedicated team of clinicians and staff who are willing to take on a new field, be flexible, and understand the need to progress slowly but in the progressive direction.
Severe lymphatic disorder resolved with MEK inhibition in a patient with noonan syndrome and SOS1 mutation.