HPI

Ms. PC is a 49 year old white female with Non-Hodgkin’s Lymphoma who presented for her second intensification treatment with Idarubicin. The patient had undergone several courses of chemotherapy in the past and is status post bone marrow transplantation in January, 1994. The patient has undergone XRT as well. Prior to admission, the patient described feelings of numbness in her right hand. Her right internal jugular Port-A-Cath was removed and replaced by a right internal jugular Hickman catheter. A small kink was noted at the entry site, but the catheter was functional.

PMH

NHL diagnosed in 1990

s/p BMT in 1/1994

Medications

Premarin

Provera

MVI

Physical Exam

VS 97.3, 79, 18, 90/50

Gen: NAD

HEENT: unremarkable

CV: Reg rhythm, no murmurs

Lungs: clear to auscultation

Abd: soft, nontender

Ext: no edema in upper or lower extremities

Laboratory Data

SMAC normal

CBC: Hg 11.7, platelets 153

Coags: normal

Previous Radiological Studies

Ultrasound: bilateral subclavian occlusions

Venogram: chronic occlusion of the left subclavian, bilateral brachiocephalics and left internal jugular stenosis

Hospital Course

Twenty four hours after placement of new Hickman catheter, the patient presented with symptoms of upper extremity swelling and facial edema.

The use of central venous catheters has expanded rapidly over the past two decades. Temporary central venous catheters are widely used for invasive monitoring, intravenous access for large volume infusions, access for multiple intravenous medication administration and when excessive phlebotomies are required particularly in thrombocytopenic patients. Although almost all temporary central venous catheters develop a thrombus to some degree, it is uncommon for these lines to develop obstructive thrombi. More often, these catheters develop fibrin sleeves that can lead to the dysfunction of the catheter and require its removal. Otherwise, these catheters may be removed due to infectious complications.¹

Permanent central venous catheters are also widely used, particularly for cancer patients and other chronically ill patients requiring home intravenous antibiotics, medications or hyperalimentation. The advantages for administration of chemotherapy through central venous catheters include reduced risk of multiple superficial infections, thrombi from peripheral intravenous access, chemotherapy infiltration, excessive bleeding from phlebotomy sites and the preservation of the peripheral venous system over a long period of time. In addition, the long life of the permanent central venous catheters reduces the risk and complications of using multiple temporary catheters. The use of permanent central venous catheters has also increased in medical and surgical patients who require long term medical management or intravenous hyperalimentation, especially in the HIV population.

Complications of central venous catheters include infection, thrombosis, pulmonary embolism, air embolizations as well as bleeding and hemo/pneumothorax from insertion. The most common complications involve infections and thrombosis or catheter dysfunction. The management of central venous catheter thrombi can be difficult.

Central Venous Thrombosis

Prior to the widespread use of central venous catheters, most central venous thrombi were thought to develop from effort or stress induced vascular damage. Patients often presented with upper extremity swelling and related a history of exertion or trauma several days prior to the symptoms. Often, these patients were also found to have a corresponding anatomic cause including cervical ribs, thoracic outlet obstructions and other etiologies.² Other obstructions may be due to mediastinal lymphomas, tuberculosis and aneurysms. See table 1.

Adapted from Horattas et al. Changing Concepts of DVT of Upper Extremity. Surgery 1988; 104: 561-567.

Central Venous Catheters

Central venous catheters were initially introduced in 1952. This heralded the age of invasive hemodynamic monitoring and intravenous access especially in the intensive care setting. Temporary central venous catheters, however, were introduced for use in malnourished patients in 1969.³ Prior to this, the most efficient way of administering hyperalimentation without the destruction of the peripheral venous system was through the construction of A-V fistulas.⁴ Unfortunately, A-V fistulas were prone to clotting and dysfunction despite various attempts to improve these systems with grafts. Placing temporary central venous catheters reduced the difficulties associated with repairing dysfunctional A-V fistulas. Thus the initial application of long term central venous catheters was to deliver hyperalimentation to patients with malabsorption following multiple bowel resections, patients with severe pancreatic disease and for children with the "short gut" syndrome.³

In 1973, J. W. Broviac described the technique for placing superior vena cava catheters by placing an all-Silastic^® catheter into the superior vena cava via the subclavian vein after tunneling under the skin and securing the catheter with a Dacron^® cuff.⁵ Hickman later modified this catheter in 1975 by increasing the internal diameter and wall thickness to allow for more rapid infusion and permit venous blood drawing.⁶

Catheter Types

There are three widely used types of central venous catheters. An increased incidence of thrombosis with one catheter over the other does not appear to exist.⁷ The Hickman catheter is generally used when intensive, continuous long term therapy is required. The Hickman catheters are open ended and require a clamp externally to prevent air embolization. A closed valve catheter, the Groshong catheter, was later introduced; this has a pressure sensitive two way valve on the internal end of the catheter. When there is neutral pressure, the valve remains closed. This helps prevent backflow of blood into the catheter as well as air embolization. The third type of tunneled central venous access is subcutaneously implanted, the Port-A-Cath. This is usually implanted in upper chest or upper extremity and is associated with an infusion chamber connected to a length of silicone rubber tubing. The Port-A-Cath is usually associated with a reduced risk of infection, decreased maintenance and has less body image alteration. The disadvantages of the Port-A-Cath include the potential extravasation of drugs in the subcutaneous space, difficulty in administering large volume medications secondary to the small needle used for accessing the port, and specially trained nurses are required to access the port.

Clinical problems associated with central venous catheters include catheter dysfunction secondary to an occlusive thrombus or fibrin sleeve, upper extremity edema and superior vena cava syndromes.^8,9,10,11 The most common thrombotic complication is venous access failure due to fibrin sleeves. As these catheter tip sleeves progress, they may cause occlusion of the catheter itself. A mural thrombus may also develop. There is an estimated 28-50% incidence of catheter induced thrombosis.^12,13,14,15 Central venous catheter thrombi are asymptomatic if they develop slowly and are associated with the formation of collateral circulation. Once a thrombus is formed, recanalization of the vein is rare.^2,14 The true incidence of pulmonary embolism from upper extremity deep venous thrombi is unknown and has been considered uncommon in the past.²⁸ Recently, it is felt to be clinically significant.^2,16 Patients frequently have other reasons to explain symptoms of hypoxia, shortness of breath and pleuritic chest pain. The presence or absence of pulmonary emboli is not always investigated. Autopsies, however, suggest an increased incidence of pulmonary emboli from upper extremity deep venous thrombosis than previously recognized.¹⁶ Because of the risk for pulmonary embolism, central venous catheter thrombi usually require some form of intervention.

Pathogenesis

Several factors appear to predispose to thrombus formation. Catheter characteristics play a major role in the possible formation of a mural thrombus. Polyurethane and polyvinyl chloride catheters may be more thrombogenic than silicone catheters. Teflon catheters are stiffer and create greater vessel injury and turbulence. The presence of turbulence is associated with a greater incidence of thrombus formation.^2,14,17,18 Placement of these stiffer central venous catheters in the subclavian vein, for purposes of hemodialysis for example, are associated with greater incidence of thrombus formation or venous stenosis than placement of these catheters in the internal jugular vein. The size of the blood vessel and the type of injury to the vessel may be contributing factors. Several investigations have correlated the development of deep venous thrombosis with the circumferential size of the catheters.¹⁹ Double lumen catheters may be more responsible for thrombus formation as opposed to single lumen catheters due to the larger diameter of double lumen catheters.²⁰ Other factors contributing to thrombus formation include size of blood vessel, previous radiation therapy, presence of local tumor and the characteristics of the infusate. See table 2.

Table 2. Factors favoring mural thrombus formation

The precise pathogenesis of central venous catheter thrombosis is still uncertain. Virchow’s triad of vessel injury, blood stasis and hypercoagulable states may offer a way to review possible causes. Subclavian vein injury at the time of initial puncture may cause local venous thrombosis or an extrinsic hematoma causing obstruction of blood flow. Thrombi usually extend from the puncture site.^12,14 Venous stasis may contribute to thrombosis after fibrin accumulates on the catheter and partially obstructs venous flow. The formation of fibrin sleeves is a predictable consequence of blood exposure to an artificial surface and occurs within twenty four hours of placement.^12,21 Platelets are quickly deposited on the catheter after insertion. A longer thrombus free survival has been found in patients who were thrombocytopenic at the time of central venous catheter placement.^22,23 Standard chemotherapy has been shown to cause damage to the vascular endothelium as well as lower levels of naturally occurring anticoagulant proteins, protein C and protein S, which have been associated with clinically significant thrombotic tendencies. Other infusate medications including antibiotics and hyperalimentation may also cause endothelial damage, platelet aggregation and initiation of the coagulation cascade.

Infection may also play a role in the formation of occlusive thrombosis.^12,24 The universal fibrin sleeve formation after catheter placement may play an important role in the development of infection. The sleeve is rich in fibrin and fibronectin which may become a platform for infection with Staphylococcal epidermidis, Staphylococcal aureus and Candida albicans. Staph. aureus and Candida albicans adhere to the fibrin and fibronectin producing a coagulase enzyme that may promote thrombogenesis. Staph. epidermidis adheres to fibronectin and forms a fibrous glycocalyx that promotes thrombogenesis as well. An infected thrombus should be considered equivalent to infectious endocarditis. A septic thrombosis may lead to septicemia that persists even after the catheter is removed. However, most catheter related sepsis episodes are uncomplicated, and removal of the catheter eliminates the source of infection.

Several methods are used to efficiently and effectively diagnose central venous catheter thrombi. Foremost, the diagnosis requires a high degree of clinical suspicion. Patients may present with shoulder, arm or neck pain, tightness or swelling in the arm or hand or prominence of the superficial veins in the shoulder, neck or chest. Symptoms, however, can be subtle and are often overlooked.

Ultrasound

Once a patient is suspected to have a thrombus, several procedures can be utilized to confirm the diagnosis. Ultrasound of the subclavian and jugular veins is widely used as it is noninvasive and cost effective. Ultrasonography may not be as reliable in detecting upper extremity deep venous thrombosis in comparison to lower extremity deep venous thrombosis.²⁵ This may be due to the extensive collateral circulation found around the shoulder which can be mistaken for venous flow in the main venous system. Clavicular shadowing has been suspected to hinder vision of the proximal portion of the subclavian veins and of the superior vena cava. Although duplex imaging improves the ability to detect thrombus formation, utilizing ultrasound may fail to reveal a significant portion of central venous thrombi particularly in the proximal veins. If a thrombus is found by ultrasound, the specificity is very high. A false positive report due to artifact for example, is rarely seen.²⁵ Ultrasound, however, cannot distinguish flow obstruction from extrinsic venous compression, internal thrombotic obstruction and venous stricture.

Venography

If ultrasound does not adequately visualize the central venous system or if the thrombus is still suspected after ultrasound failed to confirm its presence, other methods can be employed. The "gold standard" for diagnosis of upper extremity deep venous thrombosis is venography. This may be performed in two ways. Contrast may be injected into the catheter itself. This may reveal a fibrin sleeve or distal central venous catheter occlusion. This is employed frequently when a catheter becomes dysfunctional. Catheter injections do not characterize a central venous thrombus proximal to the catheter tip, especially if the catheter itself is patent. Peripheral injection of intravenous contrast is preferred in order to evaluate the extent of thrombus. Venography has been shown to be highly reliable in identifying upper extremity deep venous thrombosis. Venography can also identify venous strictures and assess the extent of the development of venous collaterals. Drawbacks include contrast dye allergy, acute tubular necrosis of the kidney, and potential contrast dye induced extension of an existing thrombus. Digital subtraction techniques have reduced the amount of contrast dye required for evaluating the central venous system.

Impedance Plethysmography

Impedance plethysmography does not reliably predict the presence of central venous catheter thrombi but may reveal obstruction in a blood vessel not found by venography due to insufficient dye transmission.²⁶ The frequent presence of collateral circulation limits the sensitivity when chronic obstructive lesions are present.²⁶ Impedance plethysmography is also difficult to perform properly as it requires significant patient cooperation and relaxation.^18,27

Magnetic Resonance Imaging

Magnetic resonance imaging can visualize venous thrombi in the lower extremities and abdomen; although, experience in the thorax is limited. As with ultrasound, magnetic resonance imaging is very specific with rare false positive radiographic findings, however, the sensitivity is not very high.²⁵ Unlike ultrasound, clavicular shadowing of the proximal subclavian vein is not a factor, yet, the proximal central venous vessels are difficult to adequately visualize.

Computed Tomography

Computed tomography is less invasive than venography and may be used to evaluate the presence of a thrombus.²⁸ It is commonly used to evaluate lesions causing external compression of the central venous system, and the specificity and sensitivity of identifying central venous thrombi are unknown.

Echocardiography

Unfortunately, 2D echocardiography is not useful for the detection of central venous thrombi. Thrombus formation within the right atrium or at the right atrial-superior vena cava junction can be seen by 2D echocardiogram but most thrombi do not extend to the right atrium.²⁹ Also, it is difficult to visualize the distal portion of the superior vena cava. Doppler echocardiogram can detect abnormal flow caused by turbulence. This may occur in cases of venous obstruction. Central venous catheters themselves do not create turbulence on doppler echocardiogram. Patients with proven central venous catheter thrombi usually have abnormal flow patterns secondary to critical reduction in lumen size.³⁰ Efforts at visualizing central venous system with TEE have also been explored with better visualization of the central veins and thrombus formations.³¹ Utilization of echocardiography has been studied in hemodialysis patients who have severely limited peripheral access for venography.

Treatment

At the present time, the management of central venous thrombi related to indwelling central venous catheters is individualized. For the patient with distal occlusion of the central venous catheter from fibrin sleeve formation, several treatment options are available. If the patient does not require the catheter or if the catheter is a potential source of infection, the catheter should be removed. The fibrin sleeve is usually stripped off during this removal but rarely does this result in a significant pulmonary embolus. Other treatment options include guide wire dislodging of the fibrin sleeve, manual stripping of the catheter and thrombolytics. Bleeding complications from thrombolytics are rarely seen.

The approach to the patient with mural thrombus requires more intensive consideration. If the patient presents with acute symptoms, aggressive therapy may be required to alleviate symptoms and reduce complications. If the catheter is no longer needed, the catheter should be removed. Additional therapy may be required if symptoms persist after the removal of the catheter.³² Catheter removal is mandatory if there is coexisting infection with a mural thrombus or if the patient does not improve with other forms of therapy. If patients have occluded all of the major veins in the upper central venous system, permanent lumbar central venous catheters can be placed. These are generally associated with increased risk of thrombosis and serious pulmonary emboli.³³

Anticoagulation Therapy

If the symptoms are mild or if the obstruction is chronic, routine anticoagulation is often preferred. Although anticoagulation with heparin does not offer fibrinolytic degradation of the thrombus itself, it may be effective in preventing the thrombus from extending. Long term anticoagulation is recommended to discourage thrombus extension, but progression of a thrombus has been shown despite adequate heparin therapy.^2,2132,34 The presence of an extrinsic compression factor often leads to failure of anticoagulation therapy.³⁵ In addition, anticoagulation is contraindicated in many patients with central venous thrombi secondary to thrombocytopenia or other bleeding disorders. These patients may then have potentially greater risks for bleeding complications. Low molecular weight heparin has been suggested to be effective at prevention of clot propagation without the increased risk of bleeding found with the use of standard heparin.³⁶

Thrombolytic Therapy

Thrombolytic therapy is effective in managing an acute thrombus formation. Thrombolytics should be considered in severely symptomatic patients or if routine anticoagulation fails. The ideal agent should restore blood flow, prevent further propagation and prevent embolization of the thrombus.²¹ Generally, thrombolytics are more effective if used within five days of onset of symptoms.^10,21 The agent of choice is usually infused into the clot itself through a separate infusion catheter placed distally through a peripheral vein.¹⁰ Active phlebitis is a relative contraindication for thrombolytic therapy. Canalization of an appropriate vessel can be difficult with phlebitis, and the inflammation causes persistent thrombogenesis which may lead to treatment failure. Patients with extrinsic venous compression by tumor or other causes also do not respond well to local thrombolytic therapy.³² With local infusion catheters, plasma fibrinogen levels remain relatively safe.³⁷ Levels should be monitored, regardless, and maintained at least 80 to 100 mg/dL. If the fibrinogen levels drop precipitously, the infusion may need to be held for several hours. Heparin is often administered during the thrombolytic therapy and occasionally for up to a week after the thrombolytic therapy until endothelial repair is obtained.³⁸ Otherwise, anticoagulation is only recommended if patients have residual thrombus.

Streptokinase

Streptokinase was the first thrombolytic agent to be used successfully in the treatment of central venous catheter thrombosis. During thrombolysis, streptokinase requires plasminogen as a cofactor and substrate. The streptokinase/plasminogen complex then cleaves another plasminogen molecule into plasmin. The use of streptokinase has declined over the past few years as newer and potentially more effective agents have been introduced. There is an increased incidence of severe complications with streptokinase including intracranial hemorrhage, anaphylaxis and death. Streptokinase is effective at clot lysis, but a longer time period may be needed. ⁹ The usual dose given is 250,000 units over 30 minutes followed by a constant infusion of 1000 units per hour. The infusion is generally maintained for 72 hours.

Urokinase

Urokinase is currently the most popular thrombolytic agent. It acts on plasminogen directly to form plasmin. Urokinase has a lower incidence of bleeding complications, pyrexia, allergic reactions, and it has a shorter time to clot lysis than streptokinase. Urokinase is administered at the site of the thrombus using lower doses than would be necessary for systemic thrombolysis. Urokinase is not as effective when used systemically as collateral circulation often bypasses the thrombus.^10,32 The standard dose of urokinase is 1000 units/kg/hour.

Recombinant Tissue Type Plasminogen Activator

The use of recombinant tissue type plasminogen activator is also being investigated. Tissue plasminogen activator converts plasminogen into plasmin in the presence of thrombus-bound fibrin. Neither streptokinase nor urokinase require the presence of thrombus-bound fibrin to activate plasminogen into plasmin. Theoretically, tissue plasminogen activator should have selective local action even when given systemically leading to fewer bleeding complications.³⁶ Urokinase and streptokinase therapy is more effective when delivered directly into the clot and have a greater risk of bleeding when given systemically. The success of tissue plasminogen activator on clot lysis may be less dependent on the duration of the thrombosis than other thrombolytics.¹² The dose routinely used is 100 mg over two hours. However, tissue plasminogen activator can be given as local infusion with a five mg bolus and one to two mg per hour infusion rate until results are seen.

Percutaneous Transluminal Angioplasty

Angioplasty of residual thrombus or stenosis is gaining increasing application as part of the treatment plan for central venous catheter thrombi. Angioplasty may result in a more patent vessel without the risk of complications associated with thrombolytics and anticoagulants. Often angioplasty is performed after thrombolytics when residual thrombus is seen or stenosis of the blood vessel is found and can be repeated multiple times with minimal complications.⁴³ Stents may also be placed in the involved vessel after angioplasty to help restore blood flow, particularly when extrinsic compression is present, and to reduce the risk of restenosis.^39,40 Stents may restenose secondary to tunica intima overgrowth of the stent itself.⁴¹ Modifications with Gortex^® are being investigated to help prevent restenosis. Angioplasty can have potential complications including dissection of the vessel wall. Complications of stent placement include stent dislodgement, migration, and stent collapse.

Venous Reconstruction

Operative reconstruction has been described as an option for obstructive thrombosis. Venous reconstructions do not have equivalent patency rates as seen in arterial reconstructions. Often, collapse of the vessel occurs secondary to low venous pressures.^10,43 Angioplasty is gaining favor over venous reconstruction as it can be done as an outpatient, requires no anesthesia and can be repeated if necessary without major morbidity.⁴⁴

Efforts to prevent thrombosis have also been studied. Low dose coumadin may reduce the incidence of thrombus formation.^42,44 Ongoing research regarding the benefits of low dose coumadin are still being conducted. Currently, Dr. Andes at North Carolina Baptist Hospital is currently leading a study of low dose coumadin vs. placebo for newly placed central venous catheters. Prevention of thrombus formation can also be improved with aseptic technique and radiological assurance of proper catheter tip placement. Occasionally, ultrasound is useful as a screening test prior to catheter placement to assess the patency of a vessel.^45,46 This may avoid placement of a catheter in vessels with residual thrombus or stenosis especially in patients with prior catheter placements in the area. Preference of placing stiffer catheters (i.e. temporary catheters) in the internal jugular vein as opposed to the subclavian veins may also reduce the risk of venous stenosis. Aspirin is routinely given to patients, if not contraindicated, to prevent immediate deposition of platelets to the areas that have been manipulated by angioplasty or stent placement.²³ Aspirin may also be given to the patient during their initial catheter insertion. Platelet deposition after catheter placement may play a significant role in the development of a thrombosis as a longer thrombus free interval is seen in patients who were thrombocytopenic at the time of catheter placement.

Central venous catheters are commonly used in patients requiring long term intravenous therapy. The use of these catheters has lessened the morbidity and improved quality of life for patients requiring chemotherapy, home intravenous antibiotics or medications and long term hyperalimentation. With the increased use of central venous catheters, a greater incidence of central venous thrombi has been seen. Emphasis in determining the best diagnostic tools and the most effective treatment options may help reduce the morbidity potentially associated with central venous thrombi.

Special Thanks to Dr. James Perry and Dr. John Regan for their guidance and support.

References