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Long-term complications of central venous catheters in children
SYMPOSIUM: INTENSIVE CARE
Long-term complications of central venous catheters in children
Introduction The use of central venous catheters (CVCs) has been a tremendous improvement in the care of critically ill children and children with chronic conditions. In critically ill children, CVCs are used to administer continuous vasoactive agents, to perform fluid resuscitation and to monitor cardiovascular status. In children with chronic conditions, CVCs are used to administer medications, total parenteral nutrition (TPN) and blood products. However, use of CVCs can have serious, sometimes lifethreatening complications. Complications may occur during CVC placement (short-term complications) or during maintenance of the CVC (long-term complications). Long-term complications can be divided into thrombotic and infectious. Because of the increasing use of CVCs outside of the hospital in the ambulant settings, general paediatricians may also be confronted with longterm complications. This review provides an overview of the clinical use of CVCs and the recognition, prevention and management of the possible thrombotic and infectious complications.
JJ Sol JBM van Woensel CH van Ommen AP Bos
Abstract The use of central venous catheters (CVCs) in children is increasing. However, they can cause serious, sometimes life-threatening complications. This review discusses the clinical use of CVCs in children and the thrombotic and infectious complications related to this type of catheter. Percutaneously placed short-term CVCs have been the primary means of central venous access in critically ill children. Long-term CVCs are often used in children with cancer and in those who require total parenteral nutrition. The incidence of CVC-related venous thrombosis (CVC-VT) varies widely and depends on underlying conditions and the diagnostic tests used. Thrombotic symptoms include loss of CVC patency, swelling, pain, discoloration of the limb and signs of CVC-related bloodstream infection (CRBSI). Clinical suspicion of CVC-VT requires urgent proper assessment of the vessel. In cases of CVC-VT, the CVC can remain in situ only if access to the vessel is still required and the CVC is patent. Initial anticoagulation therapies include low molecular weight or unfractionated heparin, followed by vitamin K antagonists or low molecular weight heparin for a minimum of 3 months. The clinical symptoms of CRBSI are scarce and nonspecific. Definite diagnosis is made by examining simultaneous peripheral and CVC blood cultures. There is no clear evidence on whether a CVC should be removed on suspicion of CRBSI. Empirical antibiotic therapy should cover both Gram-positive and Gram-negative micro-organisms.
Use of CVCs CVCs take a direct route into large central veins and may have multiple lumens. The main advantage of CVCs is that they allow larger volumes to be delivered to patients in a short time, compared with peripheral intravenous catheters. In addition, they allow the delivery of medications that may be irritating to peripheral veins due to their concentration or chemical composition (e.g. some chemotherapeutic agents, TPN). CVCs can also be used to measure central venous pressure in acute clinical situations. A wide variety of CVCs are used in children. Percutaneously placed internal jugular, subclavian and femoral short-term (1–14 days) CVCs are the primary means of central venous access in paediatric critical care, and they can be placed at the bedside using the Seldinger technique. Long-term CVCs (e.g. Hickman lines, Broviac catheters) can remain in place for more extended periods. These CVCs are inserted into the target vein (usually the subclavian or internal jugular vein) and then tunnelled under the skin to emerge a short distance between the insertion point and the vessel. Some long-term CVCs (often referred to by brand names such as Port-a-Cath and MediPort) involve a small, subcutaneously implanted reservoir (port). The catheter is usually inserted into the internal jugular or subclavian vein and tunnelled under the skin of the chest wall, where the port is situated. The port has a silicone membrane that can be accessed by puncturing the overlying skin.
Keywords paediatric; central venous catheter; complication; therapy; prevention
J J Sol MD is at the Paediatric Intensive Care Unit, Emma Children’s Hospital /AMC, Amsterdam, Netherlands.
Thrombotic complications A 1.5-year-old girl with chronic intestinal pseudo-obstruction syndrome with urinary tract involvement was completely dependent on parenteral nutrition. She was referred to our hospital because of occlusion of her right femoral vein CVC (Broviac). In the previous 16 months, five CVCs had been placed in both subclavian veins and the right femoral vein, but they had to be removed due to loss of patency. No proper evaluation of these occlusions was performed. We replaced the current CVC
J B M van Woensel MD is at the Paediatric Intensive Care Unit, Emma Children’s Hospital/AMC, Amsterdam, Netherlands. C H van Ommen MD is at the Department of Paediatric Hematology, Emma Children’s Hospital/AMC, Amsterdam, Netherlands. A P Bos MD is at the Department of Paediatric Intensive Care Unit, Emma Children’s Hospital/AMC, Amsterdam, Netherlands.
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SYMPOSIUM: INTENSIVE CARE
Massicotte et al.7 reported an incidence of 16% for CVC-related pulmonary embolism. However, the incidence of pulmonary embolism is likely to have been underestimated because of a low index of suspicion.11 In cases of unexplained dyspnoea, tachypnoea or increased oxygen need in a patient with a CVC, pulmonary embolism should be excluded immediately. Although various studies have confirmed the correlation between bloodstream infections and CVC-VT, the direction of this correlation remains unclear.12–14 Pain, swelling, varicose veins, pigmentation and occasional ulceration of the leg are symptoms of PTS, which occurs in about 60% of children with radiologically documented VT even in the absence of clinically overt CVC-VT in the acute phase.15,16 The efficacy of interventions to prevent PTS in children (e.g. elastic compression stockings) is unclear.5
with a new one in the right femoral vein. After this, the patient developed fever and a swollen, painful right leg. Ultrasonography revealed venous thrombosis (VT) from the femoral vein up to the inferior caval vein. She was treated with anticoagulation therapy and antibiotics, and the CVC was removed. Venography showed occlusion of the right subclavian vein with collateral vessels. Finally, a new CVC was inserted in the left subclavian vein. After 3 months of anticoagulation therapy, vitamin K antagonist prophylaxis to prevent CVC-related thrombosis was started. Loss of CVC patency Loss of CVC patency is usually caused by either VT or obstruction of the CVC (e.g. due to intraluminal thrombosis). Both types of thrombosis can impair infusion and withdrawal of blood. Loss of patency caused solely by luminal obstruction of the CVC can be treated with local low doses of a thrombolytic agent such as urokinase or r-tissue plasminogen activator.1 Use of these agents requires close communication with a specialised centre.
Management: Guidelines for the treatment of thromboembolic events in children are usually extrapolated from guidelines for adults. Only a few clinical trials have been conducted to determine the optimal dose and duration of therapy in children.5 In cases of CVC-VT, all CVCs that are no longer required or are non-functioning should be removed.1 Monagle et al.1 suggest that anticoagulation therapy should be started at least 3–5 days before CVC removal for CVC-VT. A CVC that is indispensable and still patent can remain in situ, but anticoagulation therapy should be started. Current best practice calls for low molecular weight heparin (LMWH) or unfractionated heparin, followed by vitamin K antagonists or LMWH for at least 3 months. Thereafter, prophylaxis might be considered until the CVC is removed.1
CVC-related VT Several mechanisms play a role in the development of CVCrelated VT (CVC-VT), including injury to the vessel wall by the CVC or infused substances, compromised blood flow and thrombogenic effects of the CVC material. Formation of mural thrombi that adhere to the vessel wall usually compromises blood flow in the vein.2 In the acute phase, this may lead to swelling, pain and discoloration of the extremity. Although loss of CVC patency usually occurs concomitantly, it may also occur at a later stage. Overt collateral circulation in the skin may be a late symptom. Suspicion of CVC-VT requires urgent proper evaluation of the patency of the vessel. The incidence of CVC-VT varies widely depending on the underlying condition (e.g. malignancy, trauma) and the diagnostic tests used.1 Studies relying on clinical symptoms only have reported incidences as low as 0–10% in children. Using more sensitive radiological methods or systematic radiological screening, other studies have reported incidences as high as 65%.2–4
Prevention: Few studies have investigated the efficacy and safety of preventive antithrombotic strategies in children. A randomised controlled trial reported no beneficial prophylactic effect of LMWH for CVC-VT in children in clinical and ambulatory settings. This result should be interpreted with caution, however, as the study was underpowered due to premature closure resulting from a slow recruitment rate.17 Two studies have reported that the use of heparin-coated CVCs significantly reduces the incidence of CVC-VT in critically ill children.18,19 The results of several other studies cannot be generalised, as they were performed in specific patient groups. For example, it has been shown that children who receive TPN at home might benefit from vitamin K antagonists.20 One study has reported that prophylactic antithrombin threatment failed to reduce the incidence of CVC-VT in paediatric patients with acute lymphoblastic leukaemia who were treated with L-asparaginase.21
Risk factors: Use of CVCs is the most important risk factor for VT in children.5 Several studies have shown that as many as 60% of venous thrombotic events in children are associated with catheters.1,6 Reports on the risk of CVC-VT associated with the site of insertion are contradictory. Some studies have found that CVCs in the upper central veins are associated with higher incidences of VT than CVCs in the femoral veins, and another study found the risk to be higher for femoral and subclavian CVCs than for brachial and jugular CVCs.7–9 The latter study also reported that the incidence of VT was independent of both the duration of CVC placement and the type of CVC.9 In contrast, Ingram et al. found that the incidence of VT was higher with external than with indwelling CVCs (ports).10
Infectious complications A 3-year-old boy was admitted to the paediatric ICU for mechanical ventilation for respiratory insufficiency caused by extreme abdominal distension due to a large abdominal neuroblastoma. A CVC was placed in the left subclavian vein, without complications. After 10 days, the patient developed a continuous fever as high as 39 1C without localising signs or symptoms. Infection at the insertion site of the CVC was not suspected. The C-reactive protein (CRP) level was 255 mg/L.
Complications of CVC-VT: Possible complications of CVC-VT include potentially fatal pulmonary embolism, CVC-related bloodstream infection (CRBSI), caval vein syndrome, chylothorax and post-thrombotic syndrome (PTS).
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SYMPOSIUM: INTENSIVE CARE
After collection for blood cultures from the CVC and peripheral venous puncture, vancomycin and gentamicin were started. After 1 day, gentamicin-susceptible Escherichia coli had grown in both blood cultures. Because the fever persisted and the CRP remained elevated, the CVC was removed, after which the temperature and CRP normalised within 2 days. E. coli also grew in a culture from the tip of the CVC.
Studies in adults have shown that CVCs impregnated with antimicrobial or antiseptic agents can effectively reduce colonisation.37–39 Prophylactic use of systemic antibiotics at the time of CVC placement does not reduce the incidence of CRBSI.24 Vancomycin is the anti-infective agent that has been most extensively studied as a lock or flush solution for patients requiring long-term central access.24,36,40 A Cochrane systematic review shows that flushing long-term tunnelled CVCs in paediatric oncology patients with a vancomycin/heparin solution can reduce the incidence of Gram-positive infections.23 However, the development of vancomycin-resistant micro-organisms is an important disadvantage.
Interpretation of studies on the incidence of and risk factors for CRBSI is hampered by inconsistency of definition. Studies from the USA report a mean incidence of about seven cases of CRBSI per 1000 catheter days in patients admitted to paediatric ICUs.22 Incidences of between one and four cases of CRBSI per 1000 catheter days have been reported for paediatric haematology patients.10 The most common pathogens are coagulase-negative staphylococci.22,23 The clinical symptoms of CRBSI are usually non-specific and scarce, and fever is often the only sign.24,25 Although local redness and swelling are more specific, they are absent in most cases of CRBSI. The most appropriate method of diagnosing CRBSI is by simultaneous blood cultures from a peripheral vein and the indwelling CVC, with the CVC sample becoming positive at least 2 hours before the peripheral vein sample.24,26
Conclusion The incidence of CVC-VT varies widely and depends on underlying conditions and the diagnostic tests used. Signs and symptoms of CVC-VT include loss of CVC patency, swelling, pain, discoloration of the extremity and CRBSI. Suspicion of CVCVT necessitates urgent evaluation of the patency of the vessel. Possible complications of CVC-VT include potentially fatal pulmonary embolism, CRBSI, caval vein syndrome, chylothorax and post-thrombotic syndrome. Anticoagulation therapy for a minimum of 3 months is mandated. Interpretation of studies regarding the incidence of and risk factors for CRBSI is hampered by inconsistency of definition. Clinical symptoms of CRBSI are usually scarce and non-specific. Definite diagnosis of CRBSI is by simultaneous peripheral and CVC blood cultures. Although evidence is lacking on the necessity of removing the CVC in cases of CRBSI, the persistence of symptoms of infection despite antimicrobial treatment mandates removal. Empirical antibiotic therapy should cover both Gram-positive and Gram-negative micro-organisms. Data on the efficacy of prevention of both CVC-VT and CRBSI in children are scarce and preclude the development of evidence~ based recommendations.
Risk factors: Most hospital-acquired bloodstream infections in children are associated with the use of CVCs.22,24 Risk factors include neutropenia, admission to the paediatric ICU, mechanical ventilation, pre-existing infections from other sources, the presence of implanted devices, TPN, prolonged dwell time and, particularly, frequent manipulation of the CVC.27–30 The risk of CRBSI in percutaneously placed CVCs in the paediatric ICU setting increases significantly after 7 days.31 There seems to be no relationship to the insertion site, catheter type or number of lumens.22,32,33 Management: There is no clear evidence on whether a CVC should be removed on suspicion of CRBSI. In an excellent review, McGee et al. developed a guideline for this problem in adults. To the best of the present authors’ knowledge, there are no evidencebased guidelines for children.34 The threshold for removing CVCs in children should be higher because of the difficulty of reestablishing access to central veins. However, if the clinical condition does not improve within a few days after the administration of antibiotics, CVC removal must be considered. In such cases, a culture from the CVC tip is recommended to support the diagnosis.26 Empirical antibiotic treatment should cover both Gram-positive (particularly coagulase-negative staphylococci and Staphylococcus aureus) and Gramnegative micro-organisms.34 De Jonge et al. recommend CVC removal in children with CRBSI caused by fungi or Gram-negative bacteria.35
REFERENCES 1 Monagle P, Chan A, Massicotte P, Chalmers E, Michelson A D. Antithrombotic therapy in children: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: S645–87. 2 Journeycake J M, Buchanan G R. Thrombotic complications of central venous catheters in children. Curr Opin Hematol 2003; 10: 369–74. 3 Revel-Vilk S. Central venous line-related thrombosis in children. Acta Haematol 2006; 115: 201–6. 4 Andrew M, Marzinotto V, Pencharz P et al. A cross-sectional study of catheter-related thrombosis in children receiving total parenteral nutrition at home. J Pediatr 1995; 126: 358–63. 5 Journeycake J M, Manco-Johnson M J. Thrombosis during infancy and childhood: what we know and what we do not know. Hematol Oncol Clin North Am 2004; 18: 1315–38. 6 Richardson M W, Allen G A, Monahan P E. Thrombosis in children: current perspective and distinct challenges. Thromb Haemost 2002; 88: 900–11.
Prevention: Important strategies for preventing CRBSI include the use of maximum sterile techniques during insertion, standardised and diligent CVC maintenance and care, selection of the proper CVC (short-term vs long-term) and the avoidance of routine CVC replacement.24,34,36
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7 Massicotte M P, Dix D, Monagle P, Adams M, Andrew M. Central venous catheter related thrombosis in children: analysis of the Canadian Registry of Venous Thromboembolic Complications. J Pediatr 1998; 133: 770–6. 8 Beck C, Dubois J, Grignon A, Lacroix J, David M. Incidence and risk factors of catheter-related deep vein thrombosis in a pediatric intensive care unit: a prospective study. J Pediatr 1998; 133: 237–41. 9 Male C, Julian J A, Massicotte P, Gent M, Mitchell L. Significant association with location of central venous line placement and risk of venous thrombosis in children. Thromb Haemost 2005; 94: 516–21. 10 Ingram J, Weitzman S, Greenberg M L, Parkin P, Filler R. Complications of indwelling venous access lines in the pediatric hematology patient: a prospective comparison of external venous catheters and subcutaneous ports. Am J Pediatr Hematol Oncol 1991; 13: 130–6. 11 Derish M T, Smith D W, Frankel L R. Venous catheter thrombus formation and pulmonary embolism in children. Pediatr Pulmonol 1995; 20: 349–54. 12 Raad I I, Luna M, Khalil S A et al. The relationship between the thrombotic and infectious complications of central venous catheters. JAMA 1994; 271: 1014–6. 13 Stillman R M, Soliman F, Garcia L, Sawyer P N. Etiology of catheterassociated sepsis. Correlation with thrombogenicity. Arch Surg 1977; 112: 1497–9. 14 van Rooden C J, Schippers E F, Barge R M et al. Infectious complications of central venous catheters increase the risk of catheter-related thrombosis in hematology patients: a prospective study. J Clin Oncol 2005; 23: 2655–60. 15 Barnes C, Newall F, Monagle P. Post-thrombotic syndrome. Arch Dis Child 2002; 86: 212–4. 16 Kuhle S, Koloshuk B, Marzinotto V et al. A cross-sectional study evaluating post-thrombotic syndrome in children. Thromb Res 2003; 111: 227–33. 17 Massicotte P, Julian J A, Gent M et al. An open-label randomized controlled trial of low molecular weight heparin for the prevention of central venous line-related thrombotic complications in children: the PROTEKT trial. Thromb Res 2003; 109: 101–8. 18 Krafte-Jacobs B, Sivit C J, Mejia R, Pollack M M. Catheter-related thrombosis in critically ill children: comparison of catheters with and without heparin bonding. J Pediatr 1995; 126: 50–4. 19 Pierce C M, Wade A, Mok Q. Heparin-bonded central venous lines reduce thrombotic and infective complications in critically ill children. Intensive Care Med 2000; 26: 967–72. 20 Newall F, Barnes C, Savoia H, Campbell J, Monagle P. Warfarin therapy in children who require long-term total parenteral nutrition. Pediatrics 2003; 112: e386. 21 Mitchell L, Andrew M, Hanna K et al. Trend to efficacy and safety using antithrombin concentrate in prevention of thrombosis in children receiving l-asparaginase for acute lymphoblastic leukemia. Results of the PAARKA study. Thromb Haemost 2003; 90: 235–44. 22 Richards M J, Edwards J R, Culver D H, Gaynes R P. Nosocomial infections in pediatric intensive care units in the United States. National Nosocomial Infections Surveillance System. Pediatrics 1999; 103: e39. 23 van de Wetering M D, van Woensel J B, Kremer L C, Caron H N. Prophylactic antibiotics for preventing early Gram-
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positive central venous catheter infections in oncology patients, a Cochrane systematic review. Cancer Treat Rev 2005; 31: 186–96. O’Grady N P, Alexander M, Dellinger E P et al. Guidelines for the prevention of intravascular catheter-related infections. Centers for Disease Control and Prevention. MMWR Recomm Rep 2002; 51: 1–29. Rijnders B J, Peetermans W E, Verwaest C, Wilmer A, Van W E. Watchful waiting versus immediate catheter removal in ICU patients with suspected catheter-related infection: a randomized trial. Intensive Care Med 2004; 30: 1073–80. Randolph A G, Brun-Buisson C, Goldmann D. Identification of central venous catheter-related infections in infants and children. Pediatr Crit Care Med 2005; 6: S19–24. Christensen M L, Hancock M L, Gattuso J et al. Parenteral nutrition associated with increased infection rate in children with cancer. Cancer 1993; 72: 2732–8. Newman C D. Catheter-related bloodstream infections in the pediatric intensive care unit. Semin Pediatr Infect Dis 2006; 17: 20–4. Odetola F O, Moler F W, Dechert R E, VanDerElzen K, Chenoweth C. Nosocomial catheter-related bloodstream infections in a pediatric intensive care unit: risk and rates associated with various intravascular technologies. Pediatr Crit Care Med 2003; 4: 432–6. Shaul D B, Scheer B, Rokhsar S et al. Risk factors for early infection of central venous catheters in pediatric patients. J Am Coll Surg 1998; 186: 654–8. Casado-Flores J, Barja J, Martino R, Serrano A, Valdivielso A. Complications of central venous catheterization in critically ill children. Pediatr Crit Care Med 2001; 2: 57–62. Nahum E, Levy I, Katz J et al. Efficacy of subcutaneous tunneling for prevention of bacterial colonization of femoral central venous catheters in critically ill children. Pediatr Infect Dis J 2002; 21: 1000–4. Shulman R J, Smith E O, Rahman S et al. Single- vs double-lumen central venous catheters in pediatric oncology patients. Am J Dis Child 1988; 142: 893–5. McGee D C, Gould M K. Preventing complications of central venous catheterization. N Engl J Med 2003; 348: 1123–33. de Jonge R C, Polderman K H, Gemke R J. Central venous catheter use in the pediatric patient: mechanical and infectious complications. Pediatr Crit Care Med 2005; 6: 329–39. Kline A M. Pediatric catheter-related bloodstream infections: latest strategies to decrease risk. AACN Clin Issues 2005; 16: 185–98. Brun-Buisson C, Doyon F, Sollet J P et al. Prevention of intravascular catheter-related infection with newer chlorhexidine-silver sulfadiazine-coated catheters: a randomized controlled trial. Intensive Care Med 2004; 30: 837–43. Ostendorf T, Meinhold A, Harter C et al. Chlorhexidine and silversulfadiazine coated central venous catheters in haematological patients – a double-blind, randomised, prospective, controlled trial. Support Care Cancer 2005; 13: 993–1000. Rupp M E, Lisco S J, Lipsett P A et al. Effect of a second-generation venous catheter impregnated with chlorhexidine and silver sulfadiazine on central catheter-related infections: a randomized, controlled trial. Ann Intern Med 2005; 143: 570–80. Safdar N, Maki D G. Use of vancomycin-containing lock or flush solutions for prevention of bloodstream infection associated with central venous access devices: a meta-analysis of prospective, randomized trials. Clin Infect Dis 2006; 43: 474–84.
r 2007 Published by Elsevier Ltd.
SYMPOSIUM: INTENSIVE CARE
Practice points
The use of CVCs in children is increasing Percutaneously placed short-term CVCs are the primary means of central venous access in critically ill children; long-term CVCs are often used in children with cancer and in those who require total parenteral nutrition CVCs are associated with thrombotic and infectious complications
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Thrombotic symptoms include loss of patency, swelling, pain, discoloration of the limb and signs of CRBSI In cases of loss of CVC patency, thrombosis or obstruction of the CVC should be excluded Clinical symptoms of CRBSI are scarce and nonspecific; definite diagnosis is made by examining simultaneous peripheral and CVC blood cultures
r 2007 Published by Elsevier Ltd.
Long-term complications of central venous catheters in children
Introduction The use of central venous catheters (CVCs) has been a tremendous improvement in the care of critically ill children and children with chronic conditions. In critically ill children, CVCs are used to administer continuous vasoactive agents, to perform fluid resuscitation and to monitor cardiovascular status. In children with chronic conditions, CVCs are used to administer medications, total parenteral nutrition (TPN) and blood products. However, use of CVCs can have serious, sometimes lifethreatening complications. Complications may occur during CVC placement (short-term complications) or during maintenance of the CVC (long-term complications). Long-term complications can be divided into thrombotic and infectious. Because of the increasing use of CVCs outside of the hospital in the ambulant settings, general paediatricians may also be confronted with longterm complications. This review provides an overview of the clinical use of CVCs and the recognition, prevention and management of the possible thrombotic and infectious complications.
JJ Sol JBM van Woensel CH van Ommen AP Bos
Abstract The use of central venous catheters (CVCs) in children is increasing. However, they can cause serious, sometimes life-threatening complications. This review discusses the clinical use of CVCs in children and the thrombotic and infectious complications related to this type of catheter. Percutaneously placed short-term CVCs have been the primary means of central venous access in critically ill children. Long-term CVCs are often used in children with cancer and in those who require total parenteral nutrition. The incidence of CVC-related venous thrombosis (CVC-VT) varies widely and depends on underlying conditions and the diagnostic tests used. Thrombotic symptoms include loss of CVC patency, swelling, pain, discoloration of the limb and signs of CVC-related bloodstream infection (CRBSI). Clinical suspicion of CVC-VT requires urgent proper assessment of the vessel. In cases of CVC-VT, the CVC can remain in situ only if access to the vessel is still required and the CVC is patent. Initial anticoagulation therapies include low molecular weight or unfractionated heparin, followed by vitamin K antagonists or low molecular weight heparin for a minimum of 3 months. The clinical symptoms of CRBSI are scarce and nonspecific. Definite diagnosis is made by examining simultaneous peripheral and CVC blood cultures. There is no clear evidence on whether a CVC should be removed on suspicion of CRBSI. Empirical antibiotic therapy should cover both Gram-positive and Gram-negative micro-organisms.
Use of CVCs CVCs take a direct route into large central veins and may have multiple lumens. The main advantage of CVCs is that they allow larger volumes to be delivered to patients in a short time, compared with peripheral intravenous catheters. In addition, they allow the delivery of medications that may be irritating to peripheral veins due to their concentration or chemical composition (e.g. some chemotherapeutic agents, TPN). CVCs can also be used to measure central venous pressure in acute clinical situations. A wide variety of CVCs are used in children. Percutaneously placed internal jugular, subclavian and femoral short-term (1–14 days) CVCs are the primary means of central venous access in paediatric critical care, and they can be placed at the bedside using the Seldinger technique. Long-term CVCs (e.g. Hickman lines, Broviac catheters) can remain in place for more extended periods. These CVCs are inserted into the target vein (usually the subclavian or internal jugular vein) and then tunnelled under the skin to emerge a short distance between the insertion point and the vessel. Some long-term CVCs (often referred to by brand names such as Port-a-Cath and MediPort) involve a small, subcutaneously implanted reservoir (port). The catheter is usually inserted into the internal jugular or subclavian vein and tunnelled under the skin of the chest wall, where the port is situated. The port has a silicone membrane that can be accessed by puncturing the overlying skin.
Keywords paediatric; central venous catheter; complication; therapy; prevention
J J Sol MD is at the Paediatric Intensive Care Unit, Emma Children’s Hospital /AMC, Amsterdam, Netherlands.
Thrombotic complications A 1.5-year-old girl with chronic intestinal pseudo-obstruction syndrome with urinary tract involvement was completely dependent on parenteral nutrition. She was referred to our hospital because of occlusion of her right femoral vein CVC (Broviac). In the previous 16 months, five CVCs had been placed in both subclavian veins and the right femoral vein, but they had to be removed due to loss of patency. No proper evaluation of these occlusions was performed. We replaced the current CVC
J B M van Woensel MD is at the Paediatric Intensive Care Unit, Emma Children’s Hospital/AMC, Amsterdam, Netherlands. C H van Ommen MD is at the Department of Paediatric Hematology, Emma Children’s Hospital/AMC, Amsterdam, Netherlands. A P Bos MD is at the Department of Paediatric Intensive Care Unit, Emma Children’s Hospital/AMC, Amsterdam, Netherlands.
PAEDIATRICS AND CHILD HEALTH 17:3
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r 2007 Published by Elsevier Ltd.
SYMPOSIUM: INTENSIVE CARE
Massicotte et al.7 reported an incidence of 16% for CVC-related pulmonary embolism. However, the incidence of pulmonary embolism is likely to have been underestimated because of a low index of suspicion.11 In cases of unexplained dyspnoea, tachypnoea or increased oxygen need in a patient with a CVC, pulmonary embolism should be excluded immediately. Although various studies have confirmed the correlation between bloodstream infections and CVC-VT, the direction of this correlation remains unclear.12–14 Pain, swelling, varicose veins, pigmentation and occasional ulceration of the leg are symptoms of PTS, which occurs in about 60% of children with radiologically documented VT even in the absence of clinically overt CVC-VT in the acute phase.15,16 The efficacy of interventions to prevent PTS in children (e.g. elastic compression stockings) is unclear.5
with a new one in the right femoral vein. After this, the patient developed fever and a swollen, painful right leg. Ultrasonography revealed venous thrombosis (VT) from the femoral vein up to the inferior caval vein. She was treated with anticoagulation therapy and antibiotics, and the CVC was removed. Venography showed occlusion of the right subclavian vein with collateral vessels. Finally, a new CVC was inserted in the left subclavian vein. After 3 months of anticoagulation therapy, vitamin K antagonist prophylaxis to prevent CVC-related thrombosis was started. Loss of CVC patency Loss of CVC patency is usually caused by either VT or obstruction of the CVC (e.g. due to intraluminal thrombosis). Both types of thrombosis can impair infusion and withdrawal of blood. Loss of patency caused solely by luminal obstruction of the CVC can be treated with local low doses of a thrombolytic agent such as urokinase or r-tissue plasminogen activator.1 Use of these agents requires close communication with a specialised centre.
Management: Guidelines for the treatment of thromboembolic events in children are usually extrapolated from guidelines for adults. Only a few clinical trials have been conducted to determine the optimal dose and duration of therapy in children.5 In cases of CVC-VT, all CVCs that are no longer required or are non-functioning should be removed.1 Monagle et al.1 suggest that anticoagulation therapy should be started at least 3–5 days before CVC removal for CVC-VT. A CVC that is indispensable and still patent can remain in situ, but anticoagulation therapy should be started. Current best practice calls for low molecular weight heparin (LMWH) or unfractionated heparin, followed by vitamin K antagonists or LMWH for at least 3 months. Thereafter, prophylaxis might be considered until the CVC is removed.1
CVC-related VT Several mechanisms play a role in the development of CVCrelated VT (CVC-VT), including injury to the vessel wall by the CVC or infused substances, compromised blood flow and thrombogenic effects of the CVC material. Formation of mural thrombi that adhere to the vessel wall usually compromises blood flow in the vein.2 In the acute phase, this may lead to swelling, pain and discoloration of the extremity. Although loss of CVC patency usually occurs concomitantly, it may also occur at a later stage. Overt collateral circulation in the skin may be a late symptom. Suspicion of CVC-VT requires urgent proper evaluation of the patency of the vessel. The incidence of CVC-VT varies widely depending on the underlying condition (e.g. malignancy, trauma) and the diagnostic tests used.1 Studies relying on clinical symptoms only have reported incidences as low as 0–10% in children. Using more sensitive radiological methods or systematic radiological screening, other studies have reported incidences as high as 65%.2–4
Prevention: Few studies have investigated the efficacy and safety of preventive antithrombotic strategies in children. A randomised controlled trial reported no beneficial prophylactic effect of LMWH for CVC-VT in children in clinical and ambulatory settings. This result should be interpreted with caution, however, as the study was underpowered due to premature closure resulting from a slow recruitment rate.17 Two studies have reported that the use of heparin-coated CVCs significantly reduces the incidence of CVC-VT in critically ill children.18,19 The results of several other studies cannot be generalised, as they were performed in specific patient groups. For example, it has been shown that children who receive TPN at home might benefit from vitamin K antagonists.20 One study has reported that prophylactic antithrombin threatment failed to reduce the incidence of CVC-VT in paediatric patients with acute lymphoblastic leukaemia who were treated with L-asparaginase.21
Risk factors: Use of CVCs is the most important risk factor for VT in children.5 Several studies have shown that as many as 60% of venous thrombotic events in children are associated with catheters.1,6 Reports on the risk of CVC-VT associated with the site of insertion are contradictory. Some studies have found that CVCs in the upper central veins are associated with higher incidences of VT than CVCs in the femoral veins, and another study found the risk to be higher for femoral and subclavian CVCs than for brachial and jugular CVCs.7–9 The latter study also reported that the incidence of VT was independent of both the duration of CVC placement and the type of CVC.9 In contrast, Ingram et al. found that the incidence of VT was higher with external than with indwelling CVCs (ports).10
Infectious complications A 3-year-old boy was admitted to the paediatric ICU for mechanical ventilation for respiratory insufficiency caused by extreme abdominal distension due to a large abdominal neuroblastoma. A CVC was placed in the left subclavian vein, without complications. After 10 days, the patient developed a continuous fever as high as 39 1C without localising signs or symptoms. Infection at the insertion site of the CVC was not suspected. The C-reactive protein (CRP) level was 255 mg/L.
Complications of CVC-VT: Possible complications of CVC-VT include potentially fatal pulmonary embolism, CVC-related bloodstream infection (CRBSI), caval vein syndrome, chylothorax and post-thrombotic syndrome (PTS).
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After collection for blood cultures from the CVC and peripheral venous puncture, vancomycin and gentamicin were started. After 1 day, gentamicin-susceptible Escherichia coli had grown in both blood cultures. Because the fever persisted and the CRP remained elevated, the CVC was removed, after which the temperature and CRP normalised within 2 days. E. coli also grew in a culture from the tip of the CVC.
Studies in adults have shown that CVCs impregnated with antimicrobial or antiseptic agents can effectively reduce colonisation.37–39 Prophylactic use of systemic antibiotics at the time of CVC placement does not reduce the incidence of CRBSI.24 Vancomycin is the anti-infective agent that has been most extensively studied as a lock or flush solution for patients requiring long-term central access.24,36,40 A Cochrane systematic review shows that flushing long-term tunnelled CVCs in paediatric oncology patients with a vancomycin/heparin solution can reduce the incidence of Gram-positive infections.23 However, the development of vancomycin-resistant micro-organisms is an important disadvantage.
Interpretation of studies on the incidence of and risk factors for CRBSI is hampered by inconsistency of definition. Studies from the USA report a mean incidence of about seven cases of CRBSI per 1000 catheter days in patients admitted to paediatric ICUs.22 Incidences of between one and four cases of CRBSI per 1000 catheter days have been reported for paediatric haematology patients.10 The most common pathogens are coagulase-negative staphylococci.22,23 The clinical symptoms of CRBSI are usually non-specific and scarce, and fever is often the only sign.24,25 Although local redness and swelling are more specific, they are absent in most cases of CRBSI. The most appropriate method of diagnosing CRBSI is by simultaneous blood cultures from a peripheral vein and the indwelling CVC, with the CVC sample becoming positive at least 2 hours before the peripheral vein sample.24,26
Conclusion The incidence of CVC-VT varies widely and depends on underlying conditions and the diagnostic tests used. Signs and symptoms of CVC-VT include loss of CVC patency, swelling, pain, discoloration of the extremity and CRBSI. Suspicion of CVCVT necessitates urgent evaluation of the patency of the vessel. Possible complications of CVC-VT include potentially fatal pulmonary embolism, CRBSI, caval vein syndrome, chylothorax and post-thrombotic syndrome. Anticoagulation therapy for a minimum of 3 months is mandated. Interpretation of studies regarding the incidence of and risk factors for CRBSI is hampered by inconsistency of definition. Clinical symptoms of CRBSI are usually scarce and non-specific. Definite diagnosis of CRBSI is by simultaneous peripheral and CVC blood cultures. Although evidence is lacking on the necessity of removing the CVC in cases of CRBSI, the persistence of symptoms of infection despite antimicrobial treatment mandates removal. Empirical antibiotic therapy should cover both Gram-positive and Gram-negative micro-organisms. Data on the efficacy of prevention of both CVC-VT and CRBSI in children are scarce and preclude the development of evidence~ based recommendations.
Risk factors: Most hospital-acquired bloodstream infections in children are associated with the use of CVCs.22,24 Risk factors include neutropenia, admission to the paediatric ICU, mechanical ventilation, pre-existing infections from other sources, the presence of implanted devices, TPN, prolonged dwell time and, particularly, frequent manipulation of the CVC.27–30 The risk of CRBSI in percutaneously placed CVCs in the paediatric ICU setting increases significantly after 7 days.31 There seems to be no relationship to the insertion site, catheter type or number of lumens.22,32,33 Management: There is no clear evidence on whether a CVC should be removed on suspicion of CRBSI. In an excellent review, McGee et al. developed a guideline for this problem in adults. To the best of the present authors’ knowledge, there are no evidencebased guidelines for children.34 The threshold for removing CVCs in children should be higher because of the difficulty of reestablishing access to central veins. However, if the clinical condition does not improve within a few days after the administration of antibiotics, CVC removal must be considered. In such cases, a culture from the CVC tip is recommended to support the diagnosis.26 Empirical antibiotic treatment should cover both Gram-positive (particularly coagulase-negative staphylococci and Staphylococcus aureus) and Gramnegative micro-organisms.34 De Jonge et al. recommend CVC removal in children with CRBSI caused by fungi or Gram-negative bacteria.35
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Prevention: Important strategies for preventing CRBSI include the use of maximum sterile techniques during insertion, standardised and diligent CVC maintenance and care, selection of the proper CVC (short-term vs long-term) and the avoidance of routine CVC replacement.24,34,36
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7 Massicotte M P, Dix D, Monagle P, Adams M, Andrew M. Central venous catheter related thrombosis in children: analysis of the Canadian Registry of Venous Thromboembolic Complications. J Pediatr 1998; 133: 770–6. 8 Beck C, Dubois J, Grignon A, Lacroix J, David M. Incidence and risk factors of catheter-related deep vein thrombosis in a pediatric intensive care unit: a prospective study. J Pediatr 1998; 133: 237–41. 9 Male C, Julian J A, Massicotte P, Gent M, Mitchell L. Significant association with location of central venous line placement and risk of venous thrombosis in children. Thromb Haemost 2005; 94: 516–21. 10 Ingram J, Weitzman S, Greenberg M L, Parkin P, Filler R. Complications of indwelling venous access lines in the pediatric hematology patient: a prospective comparison of external venous catheters and subcutaneous ports. Am J Pediatr Hematol Oncol 1991; 13: 130–6. 11 Derish M T, Smith D W, Frankel L R. Venous catheter thrombus formation and pulmonary embolism in children. Pediatr Pulmonol 1995; 20: 349–54. 12 Raad I I, Luna M, Khalil S A et al. The relationship between the thrombotic and infectious complications of central venous catheters. JAMA 1994; 271: 1014–6. 13 Stillman R M, Soliman F, Garcia L, Sawyer P N. Etiology of catheterassociated sepsis. Correlation with thrombogenicity. Arch Surg 1977; 112: 1497–9. 14 van Rooden C J, Schippers E F, Barge R M et al. Infectious complications of central venous catheters increase the risk of catheter-related thrombosis in hematology patients: a prospective study. J Clin Oncol 2005; 23: 2655–60. 15 Barnes C, Newall F, Monagle P. Post-thrombotic syndrome. Arch Dis Child 2002; 86: 212–4. 16 Kuhle S, Koloshuk B, Marzinotto V et al. A cross-sectional study evaluating post-thrombotic syndrome in children. Thromb Res 2003; 111: 227–33. 17 Massicotte P, Julian J A, Gent M et al. An open-label randomized controlled trial of low molecular weight heparin for the prevention of central venous line-related thrombotic complications in children: the PROTEKT trial. Thromb Res 2003; 109: 101–8. 18 Krafte-Jacobs B, Sivit C J, Mejia R, Pollack M M. Catheter-related thrombosis in critically ill children: comparison of catheters with and without heparin bonding. J Pediatr 1995; 126: 50–4. 19 Pierce C M, Wade A, Mok Q. Heparin-bonded central venous lines reduce thrombotic and infective complications in critically ill children. Intensive Care Med 2000; 26: 967–72. 20 Newall F, Barnes C, Savoia H, Campbell J, Monagle P. Warfarin therapy in children who require long-term total parenteral nutrition. Pediatrics 2003; 112: e386. 21 Mitchell L, Andrew M, Hanna K et al. Trend to efficacy and safety using antithrombin concentrate in prevention of thrombosis in children receiving l-asparaginase for acute lymphoblastic leukemia. Results of the PAARKA study. Thromb Haemost 2003; 90: 235–44. 22 Richards M J, Edwards J R, Culver D H, Gaynes R P. Nosocomial infections in pediatric intensive care units in the United States. National Nosocomial Infections Surveillance System. Pediatrics 1999; 103: e39. 23 van de Wetering M D, van Woensel J B, Kremer L C, Caron H N. Prophylactic antibiotics for preventing early Gram-
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positive central venous catheter infections in oncology patients, a Cochrane systematic review. Cancer Treat Rev 2005; 31: 186–96. O’Grady N P, Alexander M, Dellinger E P et al. Guidelines for the prevention of intravascular catheter-related infections. Centers for Disease Control and Prevention. MMWR Recomm Rep 2002; 51: 1–29. Rijnders B J, Peetermans W E, Verwaest C, Wilmer A, Van W E. Watchful waiting versus immediate catheter removal in ICU patients with suspected catheter-related infection: a randomized trial. Intensive Care Med 2004; 30: 1073–80. Randolph A G, Brun-Buisson C, Goldmann D. Identification of central venous catheter-related infections in infants and children. Pediatr Crit Care Med 2005; 6: S19–24. Christensen M L, Hancock M L, Gattuso J et al. Parenteral nutrition associated with increased infection rate in children with cancer. Cancer 1993; 72: 2732–8. Newman C D. Catheter-related bloodstream infections in the pediatric intensive care unit. Semin Pediatr Infect Dis 2006; 17: 20–4. Odetola F O, Moler F W, Dechert R E, VanDerElzen K, Chenoweth C. Nosocomial catheter-related bloodstream infections in a pediatric intensive care unit: risk and rates associated with various intravascular technologies. Pediatr Crit Care Med 2003; 4: 432–6. Shaul D B, Scheer B, Rokhsar S et al. Risk factors for early infection of central venous catheters in pediatric patients. J Am Coll Surg 1998; 186: 654–8. Casado-Flores J, Barja J, Martino R, Serrano A, Valdivielso A. Complications of central venous catheterization in critically ill children. Pediatr Crit Care Med 2001; 2: 57–62. Nahum E, Levy I, Katz J et al. Efficacy of subcutaneous tunneling for prevention of bacterial colonization of femoral central venous catheters in critically ill children. Pediatr Infect Dis J 2002; 21: 1000–4. Shulman R J, Smith E O, Rahman S et al. Single- vs double-lumen central venous catheters in pediatric oncology patients. Am J Dis Child 1988; 142: 893–5. McGee D C, Gould M K. Preventing complications of central venous catheterization. N Engl J Med 2003; 348: 1123–33. de Jonge R C, Polderman K H, Gemke R J. Central venous catheter use in the pediatric patient: mechanical and infectious complications. Pediatr Crit Care Med 2005; 6: 329–39. Kline A M. Pediatric catheter-related bloodstream infections: latest strategies to decrease risk. AACN Clin Issues 2005; 16: 185–98. Brun-Buisson C, Doyon F, Sollet J P et al. Prevention of intravascular catheter-related infection with newer chlorhexidine-silver sulfadiazine-coated catheters: a randomized controlled trial. Intensive Care Med 2004; 30: 837–43. Ostendorf T, Meinhold A, Harter C et al. Chlorhexidine and silversulfadiazine coated central venous catheters in haematological patients – a double-blind, randomised, prospective, controlled trial. Support Care Cancer 2005; 13: 993–1000. Rupp M E, Lisco S J, Lipsett P A et al. Effect of a second-generation venous catheter impregnated with chlorhexidine and silver sulfadiazine on central catheter-related infections: a randomized, controlled trial. Ann Intern Med 2005; 143: 570–80. Safdar N, Maki D G. Use of vancomycin-containing lock or flush solutions for prevention of bloodstream infection associated with central venous access devices: a meta-analysis of prospective, randomized trials. Clin Infect Dis 2006; 43: 474–84.
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Practice points
The use of CVCs in children is increasing Percutaneously placed short-term CVCs are the primary means of central venous access in critically ill children; long-term CVCs are often used in children with cancer and in those who require total parenteral nutrition CVCs are associated with thrombotic and infectious complications
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Thrombotic symptoms include loss of patency, swelling, pain, discoloration of the limb and signs of CRBSI In cases of loss of CVC patency, thrombosis or obstruction of the CVC should be excluded Clinical symptoms of CRBSI are scarce and nonspecific; definite diagnosis is made by examining simultaneous peripheral and CVC blood cultures
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