Catheter-related thrombosis in pediatrics. (Continuing Education Series).
Hemostasis and Fibrinolysis
Hemostasis. In order to care for patients with VADs, an understanding of the mechanisms of clot formation and dissolution is important. Hemostasis is the normal process by which bleeding stops. It is usually initiated by some degree of tissue damage with exposure of tissue factor, and it requires a complex series of interactions between blood vessels, platelets, and coagulation proteins in the plasma. The process of hemostasis not only results in fibrin deposition, but also leads to its dissolution through a fibrinolytic process as healing occurs (Diethorn & Weld, 1989).
Hemostasis develops as a combination of two phases, primary and secondary. Primary hemostasis is the process involving vascular contraction and the accumulation of a platelet plug at the site of vascular injury. The bleeding time, a crude global test, is used clinically to assess primary hemostasis. The normal range is 3 to 9 minutes (Diethorn & Weld, 1989; Gram, 1990). Secondary hemostasis leads to the development of a stable clot forming in and around the platelet aggregate to produce a firm plug at the site of vessel injury. The process of forming this clot is described as blood coagulation, which is the transformation of liquid blood into a solid gel via the formation of fibrin (secondary hemostasis).
Although coagulation is classically divided into an "intrinsic" pathway or an "extrinsic" pathway, there are interactions between the pathways, and it is likely that most hemostatic events are initiated by the extrinsic pathway (Furie & Furie, 1992). The intrinsic pathway requires only coagulation factors contained in the circulating blood, whereas the extrinsic pathway has extravascular components as well. These pathways (see Figure 1) share a "common" pathway that ends with the formation of insoluble fibrin (Diethorn & Weld, 1989; Gram, 1990). In practice, the activated partial thromboplastin time (aPTT) is used to assess intrinsic pathway, and the prothrombin time (PT) is used to assess the extrinsic pathway (Diethorn & Weld, 1989). The thrombin time measures the final common pathway, the conversion of fibrinogen to fibrin. There are other important proteins that inhibit coagulation. These include a few activated clotting enzymes and antithrombin, which inhibit thrombin protein C, and protein S, which inhibits the coagulation cofactors activated factors VIII and V (Gram, 1990).
[FIGURE 1 OMITTED]
Platelets play a number of important roles in primary and secondary hemostasis. Their main function deals with primary hemostasis, where they stick to injured vessels, aggregate at the site of the injury, and finally release important hemostatic factors (Diethorn & Weld, 1989). Platelet concentration in whole blood ranges from 150-400 K/[micro]l (Diethorn & Weld, 1989, Gram, 1990).
Fibrinolysis. Fibrinolysis is the process by which a fibrin clot is dissolved in order to restore normal blood flow as a damaged vessel heals (Diethorn & Weld, 1989; Comp, 1990). It begins shortly after the clot has formed, and it takes many days to complete the process. Clot lysis requires the enzyme plasmin (see Figure 2), which is produced when tissue plasminogen activator (t-PA) activates plasminogen that has been incorporated within the clot (Vine, 1990). Fibrin in the clot is broken down to form fibrin degradation products (FDPs), which are released into the plasma (Vine, 1990). Inhibitory proteins, such as plasminogen activator inhibitor-1 (PAI-1) and antiplasmin, help regulate the rate of fibrinolysis (Diethorn & Weld, 1989; Comp, 1990).
[FIGURE 2 OMITTED]
Venous Access in Children
Although it was initially thought that central venous access in children should be used only in the setting of IV nutrition, today these catheters are used for many purposes. The silicone catheter was discovered as a useful IV device because of its flexibility and low thrombogenicity, in the early 1970s, Broviac, Cole, and Scribner (1973) reported that the use of a silicone elastomer right atrial catheter could be used for long-term therapy. This catheter was improved over the next few years, and in 1979 the Hickman catheter was reported to be successful for long-term use (Hickman et al., 1979). The Hickman catheter gained popularity because of the development and subsequent improvement of the Dacron cuff. The Dacron cuff revolutionized central venous access by significantly improving the longevity of catheter placement. The Dacron cuff provides a subcutaneous anchor and a barrier for bacterial growth when the subcutaneous tissue heals and adheres to the cuff material. Currently there are many different companies that have made modifications on the original design of the silicone catheter.
In the 1980s, subcutaneous venous access devices (SVADs) became available that decreased the discomfort associated with catheter manipulation. They require less care/maintenance, and they are more appealing because they are not visible as compared to externally placed devices. SVADs are also associated with fewer infections (Wacker et al., 1992). SVADs consist of a subcutaneous reservoir that is attached to a silicone catheter. The reservoir, either single or double lumen, is available in several different designs and sizes and is made of titanium, stainless steel, or plastic. The reservoir has a septum made of silicone that is accessed through the skin of the patient via a non-coring needle.
More recently, percutaneously implanted central catheters (PICCs) have become popular because of the ease of insertion, which can be done by a certified registered nurse. These catheters are typically used for short-term therapy of approximately 30-45 days (Hadaway, 1998).
The decision to insert a VAD in an infant or child is driven by patient need, access to veins, ability to care for the device at home, and length of therapy. Once a VAD is determined to be necessary, the decision for device type must also be patient driven. For example, for patients who only need long-term but intermittent venous access, the ease of care, improved self-image, and lower rate of complications make the SVAD the catheter of choice. However, patients who require continuous infusion and frequent, multiple access are best managed with external/tunneled catheters. In some children, the fear of "needle sticks" may make the external/tunneled catheter the better choice.
Studies have been conducted to determine the rate of complications in the different types of catheters used in the pediatric setting (see Table 1). in a prospective study, 322 external catheters were placed in 272 infants and children. Of these, 128 (48%) of the catheters were needed for hemodynamic monitoring, 61 (22%) for lack of peripheral access, 36 (13%) for nutritional support, and 33 (13%) for resuscitation. The authors reported that there were 21 (6%) noninfectious complications and 39 (12%) cases of infections (Casado-Flores et al., 1991). In a similar study, 149 SVADs were placed in 134 patients. Of these, there were 12 (8%) infections and 7 (5%) due to clot. Indications for this group was for the administration of chemotherapy (Munro et al., 1999). A 3-year study of PICC lines by Crowley, Pereira, Harris, and Becker (1997) prospectively collected data on 486 successfully placed PICC lines. Of these, there were 41 (8%) blocked/clotted catheters and 9 (2%) infections. The majority of the catheters were placed for the administration of antibiotics (87%) and nutritional support (8%).
It is clear that thrombotic and infectious complications comprise the largest percentage of venous access complications in infants and children. Table 1 lists a selection of studies detailing three of the most common VADs placed in pediatric patients (SVADs, PICCs, and external/tunneled catheters). Overall, PICC (1%) catheters report the lowest rate of infections followed by SVADs (8%) and external/tunneled catheters (18%). When considering thrombotic risk, PICCs report a higher percentage of thrombosis (8%) with ports (4%) and tunneled/external (3%) catheters being about equal. Overall, this series of studies report clots/thrombosis as 5% and an infection rate of 9%.
Occlusion of a VAD is classified in two ways, a complete occlusion or partial occlusion (withdrawal occlusion). A complete occlusion is defined as the inability to infuse or withdraw fluid. A blood or fibrin clot is generally the cause. Other causes of lost patency include a drug precipitate, catheter malposition, anatomic obstruction by tumors, and kinked or cracked tubing. Withdrawal occlusion occurs when a blood return becomes sluggish or absent. The most common cause is a fibrin sheath encapsulating the catheter tip. This obstruction works as a one-way valve, allowing easy infusion of fluid but making blood withdrawal impossible or difficult. The ability to infuse through the catheter with a fibrin sheath obstruction occurs because the fluid goes into the catheter, flows out the tip, fills the fibrin sheath and backtracks along the outside of the catheter, and escapes into the circulation around the edges of the fibrin sheath or a hole in the fibrin sheath. However, when negative pressure is applied during an attempt to withdraw blood, the fibrin sheath is sucked against the tip of the catheter, blocking flow of blood into the cannula (see Figure 3).
[FIGURE 3 OMITTED]
Fibrin sheath formation on catheters was first described in the literature in 1964 when incidental autopsy findings of fibrin deposits on indwelling subclavian catheters were noted (Motin, Fischer, & Evreux, 1964). A concern was raised about the possibility of embolizing clots upon removal of the catheters. A later study found fibrin deposits on 55 of 55 catheters examined at autopsy (although these clots did not necessarily cause catheter malfunction) (Hoshal, Ause, & Hoskins, 1971). Later, contrast dye was injected into the catheters of 66 patients while they were being removed and simultaneously visualized using fluoroscopy, it was noted that 42% of the patients had a fibrin sheath obstructing their catheters (Brismar, Haedstedt, & Jacobson, 1981). Subsequently, other researchers have made similar observations (DeCicco et al., 1997; Horne & Mayo, 1997).
The consequences of fibrin sheath obstruction range from being negligible to being extremely dangerous. Most commonly, there is the elimination of an important catheter function, such as blood withdrawal or drug administration. Secondly, fibrin sheaths can be seeded with bacteria, and microorganisms can be disseminated into the blood stream when the catheter is flushed or manipulated to assess if there is a blood return (DeCicco et al., 1997). Drug extravasation also can occur as a consequence of fibrin sheaths. Fibrin deposition can develop or grow from the venous entry point and encase the entire catheter (Mayo, Pearson, & Horne, 1997). If a fibrin sheath organizes along the entire length of the catheter (see Figure 4), there is a potential risk of extravasation, with fluid backtracking along the outside portion of the catheter and exiting out of the venous entry point and into the chest wall (Diekmann & Ransom, 1985; Mayo, 1998; Mayo & Pearson, 1995).
[FIGURE 4 OMITTED]
Often, the first sign that a fibrin sheath is present is withdrawal occlusion, realized as an absent or sluggish blood return. Treatment for persistent withdrawal occlusion (PWO) traditionally had been the instillation of 1 to 2 mL (5,000 to 10,000 units) of urokinase (Abbokinase Open-cath, Abbott Phamaceuticals, Abbot Park, IL) (Herbst, Kline, & McKinnon, 1998). However, urokinase is no longer available for use in catheter clearance due to manufacturing concerns by the Food and Drug Administration (FDA) (FDA, July 1999). Recently, investigations on the use of recombinant tissue plasminogen activator (t-PA, Genentec, Inc., South San Francisco, California) has shown it to be just as or more effective for the treatment of PWO. A randomized, double-blind comparison of t-PA and urokinase in 50 central venous catheters with radiographically documented occlusion by thrombus was reported (Haire, Atkinson, Stephens, & Kotulak, 1994). A dose of either 2 mg t-PA (1mg/mL) or urokinase 2 mL (5,000 units/mL) was instilled into the catheters and allowed a 2-hour dwell time. A second dose was administered if catheter function was not restored with the first dose. Catheter function was restored in 25 of the 28 (89%) catheters treated with t-PA and in 13 of 22 (46%) catheters in the urokinase group (p = 0.013). The authors concluded that a dose of 2 mg of t-PA restored catheter function more reliably and dissolved thrombi faster than twice the usual recommended dose of urokinase for catheter clearance (Haire et al., 1994). In infants and children, the dosage has ranged from 0.5 mg (diluted in saline) in children weighing less than 10 kg to 1-2 mg (1 mg/mL) in children weighing more than 10 kg (Choi, Massicotte, Chan, & Andrew, 1999).
Because of these and other studies showing significant evidence of its effectiveness, Cathflo[TM] Activase[R] (Genentech Phramaceuticals, Inc. San Francisco, CA) has been approved by the FDA for use in obstructed venous catheters. However, the studies that led to FDA approval had limited enrollment from the pediatric population. They did conclude, however, that in patients weighing greater than or equal to 10 kg to less than 30 kg, 110% of the internal lumen volume of the catheter, not to exceed 2 mg in 2 mL, should be used. If the catheter remains non-functional after a dwell time of 120 minutes, a second dose can be instilled (Cathflo Activase, Package Insert, 2001).
The safest and most effective dose of Cathflo Activase required to treat catheter-related thrombosis in infants and children remains to be determined. One study attempted to answer this question. Davis, Vermeulen, Banton, Schwartz, and Williams (2000) studied 58 pediatric and adult patients with occluded catheters (7 infants, 14 children, 37 adults). They were treated with escalating doses of 0.5 mg/mL, 1.0 mg/mL, and 2 mg/mL of t-PA. It was determined that 50 (85%) of the occluded catheters cleared with 0.5 mg/mL. Of the remaining eight catheters, five cleared after escalating to 1 mg/mL, and one (1.7%) after escalating to 2 mg/mL. The pediatric subjects were not separated to show differences. There were no complications reported that could be attributed to t-PA use. It is clear that further research is required to determine pediatric dosage and dwell time.
Fibrin sheaths may become refractory to instillations of a thrombolytic agent, and treatment has become more aggressive in order to preserve the catheter and avoid costly and painful catheter replacements. Continuous infusion therapy using thrombolytic agents has become more widely accepted for the treatment of withdrawal occlusion associated with a fibrin sheath refractory to the smaller dose installations. Although urokinase was successful by continuous infusion (Haire & Lieberman, 1992; Horne & Mayo, 1997), it is no longer available, and other agents are currently being explored as substitutes.
Despite thrombolytic therapy, catheters can remain obstructed. Catheter tip location has been documented as a variable that is associated with failure of thrombolytic therapy. In a study that treated patients with a low-dose continuous infusion of urokinase to treat catheters obstructed with fibrin sheath, 10 patients failed the infusion. Of these 10 patients, 7 had the tips of their catheters at or above the carina (Horne & Mayo, 1997). This study and others have documented the importance of catheter tip placement in the lower third segment of the SVC and have shown that the use of thrombolytic agents can eliminate the need to initially remove an occluded VAD (Corso & Wolfe, 1993; Dierks & Whitman, 1995; Kearns, Coleman, & Wehner, 1996; Lorenz, Funaki, Ha, & Leef, 2000). Further research is needed to determine the safest fibrinolytic agent as well as the most effective dose requirements in adults and children in this setting.
Central Vein Thrombosis
Central vein thrombosis can be a serious problem. If a catheter chronically rubs against the wall of a vein, it can provoke thrombosis at the site. This can also be associated with a fibrin sheath (Mayo et al., 1997). If the thrombus becomes large enough to obstruct venous blood flow, symptoms may develop into superior vena cave syndrome or SCVT.
Symptoms of SCVT include suffusion (a fullness in the head or neck), blurred vision, and vertigo. Clinical signs include edema of the neck, chest, and upper extremities; periorbital edema; facial redness; engorged jugular veins; tachycardia; shortness of breath; and sometimes a cough (Stewart, 1996).
In adults, SCVT occurs in 1-16% of catheterized veins, with asymptomatic SCVT being more common (Horne et al., 1995). Clinical signs and symptoms of SCVT include ipsilateral arm edema and/or pain, shoulder/neck pain, jugular venous distension, and visible collaterals on the chest wall (Orr & Ryder, 1993). The symptoms can be very acute or rather vague in nature depending upon the degree of collateral vein development (Horne et al., 1995).
Treatment of central vein thrombosis will often include catheter removal and anticoagulation, but patients may be left with no other central venous access if the last vein has been compromised with a clot. Thrombolytic therapy has been successful as initial treatment and increases the possibility that the venous lumen will be preserved for future catheters. Reports in the literature on the use of thrombolytic agents in infants and children for treating central vein thrombosis is limited to single case and small series reports (Ruble, Long, & Connor, 1994; Wever, Liem, Geven, & Tanke, 1995). These reports have demonstrated that thrombolytic therapy for treating venous thrombosis using a systemic infusion along with anticoagulation can be effective and is gaining popularity due to positive outcomes.
As nurses who work with adults or children, it is important to understand the mechanism of action of thrombolytic agents in order to anticipate potential bleeding complications. The objective of thrombolytic therapy is to restore catheter and/or venous patency, and this is rarely achieved with anticoagulation alone. Thrombolytic agents act by converting plasminogen to plasmin, which dissolves the clot by digesting fibrin. In treating catheter-related thrombi, the drugs are given locally to attain high level concentrations with relatively low total doses. In other settings, such as the treatment of myocardial infarction, thrombolytic agents are administered through a peripheral vein, and the drugs frequently cause hypocoagulability of the blood, a "lytic state." With the smaller doses required to treat catheter-related thrombi locally, systemic effects are less common, usually limited to a minor fall in plasma fibrinogen concentration (Kline, 1990).
Until the 1980s, streptokinase was the thrombolytic agent used for the treatment of deep venous thrombosis and pulmonary embolus as well as arterial thrombi. Streptokinase is the least expensive fibrinolytic agent, but because it is a bacterial protein, it has allergic and pyrogenic side effects, particularly with repeated exposure in patients with prior streptococcal infections. Urokinase, in contrast, is of human origin and has no allergic side effects. For this reason, urokinase was the drug of choice for treating catheter withdrawal occlusion.
Retavase[R] (Retaplase, recombinant, Centocor, Inc., Malvem, PA) is a relatively new thrombolytic agent currently being investigated for catheter clearance. Retavase is approved for use in the management of acute myocardial infarction. Retavase is a recombinant plasminogen activator that catalyzes the cleavage of endogenous plasminogen to generate plasmin (Kohnert, Rudolph, & Verheijen, 1992). Its actions are similar to t-PA, but it has a lowered affinity for fibrin. Current protocols have included instillations of 0.5 to 1 unit of Retavase into an occluded catheter and left to dwell for 15 minutes. Lower doses are also being studied (Data on file, Centocor, Inc.).
When urokinase was no longer available it became necessary to look for alternative agents for catheter related thrombosis. As discussed, Cathflo Activase has been quite recently approved by the FDA. Currently, Cathflo Activase is the only FDA-approved agent indicated for use in venous access devices obstructed by thrombus. Cathflo Activase is supplied as a sterile powder that, when reconstituted with sterile water, has a concentration of 2 mg/2 mL (Package Insert, Genentech, SanFrancisco, CA).
Clinical Considerations for Lytic Therapy
This discussion has emphasized the effectiveness of thrombolytic therapy when treating catheter-related thrombosis. Clinicians should consider certain factors prior to and during the use of infusional therapies with thrombolytic agents. Patients should be assessed for any contraindications including active bleeding, familial or acquired bleeding diathesis, neurosurgery within the last 2 months, history of stroke or intracranial metastases, hypersensitivity to the thrombolytic agent, major surgery or lumbar puncture within the last 10 days, thoracentesis or paracentesis within the last 4 days, and any abnormal coagulation parameter (PT, PTT, fibrinogen, platelets). Use in young children should be carefully considered until definitive research specific to children has demonstrated safe dosages.
The initial laboratory assessment should include coagulation parameters, CBC, and platelets. After the initial assessment, the patient should be monitored carefully. When administering thrombolytics, any recent puncture sites should be examined, especially when infusing t-PA, which has an affinity to fibrin and therefore may cause lysis of prior clots. An assessment for gingival oozing, hematuria, hemoptosis, hematemisis, positive guiacs, abdominial or flank pain, and joint swelling should be carried out. Because patients should also be anticoagulated, monitoring should include PT, PTT, fibrinogen, hemoglobin, and platelets. If there is any bleeding or oozing present, pressure should be applied, the findings reported, and any orders instituted.
Implications for Practice
Venous access devices may have some minor or serious complications of withdrawal occlusion as well as the dangerous consequences of extravasation and central vein thrombosis. Therefore, a thorough assessment of the device should be made before any medication is given, even a flush solution. Clinicians must perform a thorough assessment and identify patients at risk for catheter-related thrombosis, especially SCVT and SVCT. This can be done by determining catheter tip location in the radiology record. Catheter tips not located in the lower third of the SVC are more prone to catheter-related thrombosis. By identifying this simple information a more pro-active approach is then taken that anticipates problems related to venous access.
Thorough teaching is an important pro-active approach that is essential for care. Patients and their families should be made aware of the possibility of thrombotic complications and encouraged to report subtle symptoms to the attention of the clinician earlier. To do this, it may be helpful to institute a VAD flowsheet in order to track catheter complications. The flowsheet incorporates an assessment with questions centering around infectious complications as well as thrombotic complications. The flowsheet not only serves to track catheter progress but also serves as a constant reminder of symptoms to be aware of when they are at home. Table 2 illustrates an example of a flowsheet that incorporates typical patient questions as well as a physical assessment.
Implications for Further Research
This paper has focused on catheter-related thrombosis and the strategies used to treat them. It has been established that thrombolytic agents are effective in restoring catheter patency, but there is a need for further research to determine optimal dose requirements, dwell time for the treatment of fibrin sheath, and SCVT and SVCT in infants and children. Technique and technology strategies used to prevent infection and thrombotic complications are important research areas that are sometimes overlooked. These strategies include, surveillance of catheter tip placement, flushing protocols, positive pressure needleless systems, and the use of valved catheters. It is extremely important to be cognizant of the possibility of catheter-related thrombosis, and we must educate ourselves as well as our peers about these complications. Furthermore, we must incorporate this information into the care of our patients.
Table 1. Pediatric Studies Tracking Catheter Related Complications Total Catheter Author Date Type VAD VADs Pts Days Casado-Flores 1991 External 322 272 4 Mean Chua 1998 External 57 40 11 Mean Hruszkewycz 1991 External 17 13 32 Median Crowley 1997 PICC 486 486 20 Median Skladal 1999 Tunneled 27 22 163 Median Munro 1999 Ports 149 134 399 Median Lorenz 2000 Ports 29 28 280 Median Total (%) 1087 967 Indications for Catheter Author Clot Infection Chemo IV Nutrition Casado-Flores 3 33 36 Chua 2 18 23 Hruszkewycz 8 5 Crowley 41 9 37 Skladal 2 21 20 2 Munro 7 12 149 Lorenz 1 4 26 2 64 (5%) 102 (9%) 195 (18%) 100 (9%) Indications for Catheter Hemodynamic Author Antibiotic Fluids/Access monitoring/CPR Casado-Flores 61 161 Chua 22 12 Hruszkewycz 17 Crowley 424 Skladal Munro Lorenz 1 425 (39%) 83 (8%) 190 (17%) Table 2. Venous Access Device Assessment Flowsheet Name Catheter Location Tip Location Catheter Type Insert Date Previous Catheters Age VAD Assessment Date Date Date Date Date Question Parent or Child Y/N Y/N Y/N Y/N Y/N Infection present? Any fever/chills? Any shortness of breath? Any swelling in your/your child's face, head, neck, or eyes, especially after reclining? Any discomfort present/child complain of any discomfort? Any difficulty with the function of the catheter? Was an agent used to improve the function of your/your child's catheter? Physical Assessment Is there edema of either arm? Edema of the face or neck? Are there distended neck veins? Are there visible collateral veins on the chest wall? Is the dressing dry and intact? Is the site red, tender, or edematous? Is the catheter intact/change in catheter length? Does the catheter flush easily with normal saline? Is there a free-flowing blood return? Is there mechanical obstruction such as tight sutures or a kink in the catheter? Is there pain associated with a vigorous flush? Actions/Therapy/Outcome Note: Adapted from Mayo, 1997
Acknowledgement: The author would like to thank Dr. Margaret Rick for her enthusiastic support and editorial comments.
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Donna Jo McCloskey, MA, RN, is a Research Nurse Specialist in the Department of Laboratory Medicine, Hematology Section, Warren Grant Magnussen Clinical Center, National Institutes of Health in Bethesda, MD.
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|Author:||McCloskey, Donna Jo|
|Date:||Mar 1, 2002|
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