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doi:10.1111/jpc.12404
ORIGINAL ARTICLE
Prevention and treatment of intraluminal catheter thrombosis in children hospitalised in a paediatric intensive care unit Ana de Lorenzo-Pinto,1 Amelia C Sánchez-Galindo,2 Silvia Manrique-Rodríguez,1 Cecilia M Fernández-Llamazares,1 Sarah Nicole Fernández-Lafever,2 Miriam García San-Prudencio,2 Lucía Cortejoso1 and María Sanjurjo-Sáez1 1
Pharmacy Department and 2Pediatric Intensive Care Unit, Gregorio Marañón University General Hospital, Madrid, Spain
Aim: The aim of the study was to develop and implement a protocol for the prevention and treatment of catheter related intraluminal thrombosis in a paediatric intensive care unit. Methods: A computerised search was carried out on MEDLINE, through PubMed, using the medical subject heading ‘central venous catheter’, ‘central venous access device’, ‘central venous line’ associated with ‘occlusion’, ‘obstruction’, ‘catheter-related thrombosis’, ‘critically ill patients’ and ‘thrombolytic therapy’. References of reviewed articles were also searched for relevant titles as well as non-randomised controlled trials and series of cases when no information of higher level of evidence was available. Results: With the information gathered, a protocol for the prevention and treatment of catheter related intraluminal thrombosis was elaborated and those recommendations that best suit our environment were included. They were agreed upon by a broad panel of professionals working in the Pediatric Intensive Care Unit and the Pharmacy Department. Conclusions: Due to the variety of options available for the pharmacotherapeutic management of intraluminal catheter thrombosis, one measure to improve the quality of the therapy and to diminish the variability in the prescription could be the implementation of a protocol as described in this paper. Key words:
catheters; heparin; intensive care units; thrombolytic therapy.
What is already known on this topic
What this paper adds
1. Although thrombotic catheter occlusions are not a rare complication in children hospitalised at the Intensive Care Unit. 2. Their prevention and management have not been standardised. 3. Regarding pharmacologic treatments, little is known about the role of the new fibrinolytic agents, which have a high economic impact, but on the other hand, there exists a lack of strong evidence for their use.
1. The novelty of the article lies in the fact that it has been the first protocol in resolving these two aspects: standardisation and therapeutic positioning. 2. The use of fibrinolytic agents has been standardised. 3. An algorithm for both prevention and management of thrombotic catheter occlusions have been elaborated in order to reduce the complexity of the protocol, aid comprehension and facilitate successful implementation and validation.
Introduction Placement of central venous access devices (CVADs) is essential in the management of critically ill children and has tremendously improved the quality of care in these patients. Used for the administration of fluids, medications, total parenteral nutrition or blood products they may, however,
Correspondence: Dr. Ana de Lorenzo-Pinto, Pharmacy Department, Gregorio Marañón University General Hospital, C/Doctor Esquerdo 46, 28007 Madrid, Spain. Fax: +34915866621; email: ana.lorenzo@ salud.madrid.org Conflict of interest: None. Accepted for publication 23 May 2013.
40
also cause several mechanical, infectious and thrombotic complications.1 Catheter occlusion is defined as a partial or complete obstruction of the catheter limiting or preventing blood withdrawal, flushing the catheter, or administering parenteral solutions or medications.2 Thrombotic catheter occlusion accounts for 58% of all catheter occlusions and occurs when deposits of fibrin or blood within and around CVADs impede or disrupt flow through the catheter.3 It is also postulated that the localised vascular injury inflicted by the catheter induces a local prothrombotic state.4 Thrombotic catheter occlusion may delay or even interrupt infusion of therapy and may also contribute to the development of CVAD-related infections as blood clot serves as a culture medium for bacterial growth.5 Although the most commonly
Journal of Paediatrics and Child Health 50 (2014) 40–46 © 2013 The Authors Journal of Paediatrics and Child Health © 2013 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
A de Lorenzo-Pinto et al.
recognised complication of CVADs is infection,6 diagnosis of thrombotic events related to these devices is becoming increasingly prevalent.5 Thromboembolic events in children are still relatively rare compared to adults and this is one of the reasons for the lack of uniform recommendations available with regard to indications, drug of choice, route of administration and dosing regimen.7 Dose regimens have then been extrapolated from adult guidelines, but the fibrinolytic system in children is a dynamic, evolving system with unique features that markedly influence the response to thrombolytic agents.8 Besides, the pathophysiologic mechanisms of thrombosis in children are very different from those in adults. Although few clinical trials have studied prophylaxis of catheter-related thrombosis in children,9 the use of continuous heparin infusion or catheter locking solution with heparin have become a standard practice worldwide. The concentration of heparin lock solution has not been well established but literature shows a wide range of possible concentrations (10 U/mL up to 5000 U/mL). Higher doses of heparin seem to be more effective but with more side effects. Fibrinolytic agents such as urokinase and alteplase have been tested as a locking solution, but this option should be reserved for the treatment of intraluminal catheter thrombosis and not for prophylaxis purposes.10 It is of paramount importance to evaluate these drugs within the current therapeutic arsenal due to their high cost and the lack of strong evidence for their use. The aim of this study was to develop and implement a protocol for the prevention and treatment of CVADs intraluminal thrombosis in a paediatric intensive care unit (PICU).
Patients and Methods Study setting and population The study was carried out in the PICU of Gregorio Marañón University General Hospital, a Spanish academic hospital providing tertiary care for a metropolitan area of 700 000 people. The PICU comprises 11 beds and approximately 500 admissions per year. 35% of patients have cardiac disease, including postoperative care following heart surgery, 30% are post-operative patients following other surgeries and the remaining 35% are medical patients. The nurse/patient ratio is 1:1.
Catheter thrombosis
thrombosis’, ‘critically ill patients’ and ‘thrombolytic therapy’. The search was initially limited to meta-analysis, practice guidelines, randomised controlled trials and review papers performed on paediatric population up to March 2012. There were no language restrictions. References of reviewed articles were also searched for relevant titles as well as non-randomised controlled trials and series of cases when no information of higher level of evidence was available. Four investigators (1 physician and 3 pharmacists) conducted the literature search and extraction of relevant titles. The title and abstract of potentially relevant studies were screened for appropriateness before retrieval of the full article, where relevant. The initial search yielded 445 references. We eliminated 408 after initial screening because they were not related to central catheters, intraluminal thrombosis and/or pharmacological agents. The abstract or full text of the 37 remaining studies was evaluated (3 were meta-analysis, 3 were practice guidelines, 8 randomised controlled trials, 16 were review papers and 7 non randomised studies). With the information gathered, a protocol for the prevention and treatment of CVADs intraluminal thrombosis was elaborated and recommendations that best suit our environment were included. They were agreed upon by a broad panel of professionals working in the PICU and the Pharmacy Department. The protocol development process was guided by the goal of weighing evidence regarding effectiveness, tolerability, safety and cost and its adoption was intended to provide systematic guidance and structure regarding the array of potential prophylaxis and treatment options for this patient population. The level of evidence and the strength of recommendation of particular treatment options were weighed and graded according to predefined scales, as outlined in Table 1. Derivative products, such as algorithms, were elaborated in order to reduce the complexity of the protocol, aid comprehension, and facilitate successful implementation and validation.12–14 Such tools not only improve the standardisation of care, but might also help to coordinate the activities of all members working in the PICU.
Results
Study protocol
Prevention of catheter intraluminal thrombosis (Fig. 1)
CVADs definition: Catheter inserted into a central line, directly or through a peripheral access. Long-term catheters, tunnelled central venous devices or catheters with subcutaneous port systems. We performed a review of literature in order to identify the different pharmacological strategies available for the prophylaxis and the therapeutic management of catheter-related thrombosis in children, and their positioning in clinical practice. A computerised search was carried out on MEDLINE, through PubMed, using the medical subject heading (MeSH) ‘central venous catheter’, ‘vascular access devices’, ‘central venous line’ associated with ‘occlusion’, ‘obstruction’, ‘catheter-related
Prevention of CVADs intraluminal thrombosis with continuous heparin infusion: • Indication: To keep intravenous catheters patent for drug administration, hemodynamic monitoring and blood sampling. Evidence level Ib; Category of recommendation A.15,16 • Preparation instructions: Heparin solution at a concentration of 1 U/mL (add 0.5 mL of 1% heparin in 500 mL of normal saline). Prevention of CVADs intraluminal thrombosis with heparin lock solutions: • Indication: A heparin lock solution is indicated for the maintenance of catheters not being used for the administration of
Journal of Paediatrics and Child Health 50 (2014) 40–46 © 2013 The Authors Journal of Paediatrics and Child Health © 2013 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
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A de Lorenzo-Pinto et al.
Table 1 Quality of the scientific evidence and associated grades of recommendation11 Classification of evidence levels Ia Ib IIa IIb III IV
Evidence obtained from meta-analyses of randomised controlled trials Evidence obtained from at least one randomised controlled trial Evidence obtained from at least one well-designed, non-randomised controlled study Evidence obtained from at least one well-designed, “quasi-experimental” study Evidence obtained from well-designed, non-experimental descriptive studies such as comparative studies, correlation studies, and case reports Evidence obtained from an expert committee or expert report and/or from the clinical experience of respected authorities
Categories of recommendation A B C D
Based directly on evidence level I Based directly on evidence level II or recommendation extrapolated from level I evidence Based directly in the evidence level III or recommendation extrapolated from level I or II evidence Based directly in the evidence level IV or recommendation extrapolated from level I, II, or III evidence
Grade of recommendation
Significance
A B C
Strongly recommendable (good evidence that the measure is effective and that the benefits greatly outweigh the risks) Recommendable (at least moderate evidence that the measure is effective and the benefits outweigh the risks) No recommendation for or against (at least moderate evidence of that the measure is effective, but the level of benefit is very similar to the level of risk, and a general recommendation cannot be justified) Not recommendable (at least moderate evidence that the measure is ineffective or that the risks outweigh the benefits) Insufficient, poor quality, or conflicting evidence, and the risk–benefit ratio cannot be determined
D E Quality of the evidence
Substantial net benefit
Moderate net benefit
Small net benefit
Zero or negative net benefit
Good Moderate Poor
A B E
B B E
C C E
D D E
continuous infusion fluids. Evidence level Ia; Category of recommendation A.17–19 • Preparation instructions: Heparin solution at a concentration of 20 U/mL (commercialised product). • Volume of heparin lock solution: 2 mL. This volume will be higher (3–5 mL) for locking long-term catheters (tunnelled central venous devices, catheters with subcutaneous port systems and hemofiltration catheters). • Once the catheter has been used (after completion of drug treatment or hemodyalisis therapy), it must be flushed with 5–10 mL of normal saline and then, locked with heparin solution. Before removing the syringe, the clamp must be closed to prevent blood reflux. • If the catheter needs to be used, the locking solution will have to be aspirated and discarded. Then, the catheter should be flushed again with normal saline. ■ If blood reflux into the catheter lumen occurs after the locking procedure, the catheter must be flushed with normal saline and locked again with heparin as described above. • The same heparin lock solution can be maintained up to 7 days,20 afterwards it must be renewed. Prevention of CVADs intraluminal thrombosis with fibrinolytic lock solutions: 42
• Indication: patients with prior intraluminal thrombosis. • Dosage recommendations: the fibrinolytic agent used as the locking solution should be the same as the one used for the intraluminal thrombosis resolution. – First line: urokinase 5000 U/mL. Evidence level Ib; Category of recommendation A.21 – Second line: alteplase 1 mg/mL. Evidence level Ib; Category of recommendation A.22 • Locking volume: Administer 110% of the catheter priming volume (increasing 0.1–0.2 mL of the priming volume).23 • If the catheter needs to be used, the locking solution will have to be aspirated and discarded. The catheter should be flushed again with normal saline. • Fibrinolytic lock solution should be renewed every 48–72 hours.21,22
Treatment of CVADs intraluminal thrombosis (Fig. 2) • Diagnosis: Intraluminal thrombosis should be suspected if there are signs of no-reflow or insufficient blood flow for hemodialysis. Previously, correct placement of the catheter and whether it is bent or twisted should be checked. An
Journal of Paediatrics and Child Health 50 (2014) 40–46 © 2013 The Authors Journal of Paediatrics and Child Health © 2013 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
A de Lorenzo-Pinto et al.
Fig. 1
• •
• • •
•
Catheter thrombosis
Prevention of intraluminal catheter thrombosis.
ecography in order to exclude the presence of a blood clot inside the vessel is recommended. Treatment: 1. Flush with 5–10 mL of normal saline. If after 3 attempts the problem is not solved, administration of fibrinolytic therapy is recommended. 2. Urokinase at a concentration of 5000 U/mL. Evidence level Ib; Category of recommendation A.7,24–26 Administer 110% of the catheter priming volume (increasing 0.1–0.2 mL of the priming volume).23 Aspirate urokinase solution after 30 min and if there is not reflux, mantain for one hour. If there is no response, increase the concentration of urokinase solution to 10 000 U/mL and evaluate response at 30 and 60 min. If blood reflux into the catheter lumen occurs after the locking procedure, the locking solution will have to be aspi-
rated and discarded as well as 1–2 mL of blood, the catheter must be flushed with 5–10 mL of normal saline. 3. Alteplase at a concentration of 1 mg/mL. Evidence level III; Category of recommendation B.27–30 • Administer alteplase if treatment with urokinase fails. Administer 110% of the catheter priming volume (increasing 0.1– 0.2 mL of the priming volume).23 • Evaluate response at 30 and 60 min. • If there is no response, repeat the administration (same concentration and volume as described above). • If blood reflux into the catheter lumen occurs after the locking procedure, the locking solution will have to be aspirated and discarded as well as 1–2 mL of blood, the catheter must be flushed with 5–10 mL of normal saline. The protocol will be revised periodically as more controlled studies (level A) and new information argue for adjustment.
Journal of Paediatrics and Child Health 50 (2014) 40–46 © 2013 The Authors Journal of Paediatrics and Child Health © 2013 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
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Catheter thrombosis
Fig. 2
A de Lorenzo-Pinto et al.
Treatment of CVADs’ intraluminal thrombosis.
Discussion Catheter thrombotic occlusions and catheter-related thrombosis in critically ill children have becoming increasingly prevalent in recent years. However, the recent data are inconclusive and further research is necessary for more clearly defined guidelines 44
and recommendations with regard to both treatment and prophylaxis of catheter-related thromboembolism in paediatric patients. The novelty of the article lies in the fact that this has been the first protocol published in which antithrombotic drugs have been positioned. Clinical practice guidelines as the one
Journal of Paediatrics and Child Health 50 (2014) 40–46 © 2013 The Authors Journal of Paediatrics and Child Health © 2013 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
A de Lorenzo-Pinto et al.
elaborated by the American College of Chest Physicians31 have been available for the last 25 years, with the objective of health quality improvement. Most of them evaluate antithrombotic drugs and describe evidence, but therapeutic positioning is not included, a fact that may lead to a variability in the prescription of these agents. Therapeutic positioning as the described in this paper has been based on the authorised indications of use, commercial availability of the different agents, clinical experience, associated costs and patient specific characteristics, i.e., age or bleeding risk. Regarding fibrinolytic therapy, in our protocol urokinase has been positioned before alteplase due to its more costeffective profile.32 In order to evaluate implementation success, four aspects will be measured in the future: effectiveness and safety of the therapy followed in each case, medical staff adherence and satisfaction, aspects which are similar to those described by other authors.33,34 From our point of view, in order to achieve effective implementation of a protocol, the collaboration of a broad panel of health professionals working in the same direction is essential in order to promote multidisciplinary activities that ultimately result in better therapy for the patient.
Acknowledgements The authors thank Samantha Wilkinson for her invaluable help in editing the English manuscript.
References 1 Revel-Vilk S. Central venous line-related thrombosis in children. Acta Haematol. 2006; 115: 201–6. 2 Kerner JA Jr, Garcia-Careaga MG, Fisher AA, Poole RL. Treatment of catheter occlusion in pediatric patients. JPEN J. Parenter. Enteral Nutr. 2006; 30 (1 Suppl.): S73–81. 3 Stephens LC, Haire WD, Kotulak GD. Are clinical signs accurate indicators of the cause of central venous catheter occlusion? JPEN J. Parenter. Enteral Nutr. 1995; 19: 75–9. 4 Freytes CO. Thromboembolic complications related to indwelling central venous catheters in children. Curr. Opin. Oncol. 2003; 15: 289–92. 5 Timsit JF, Farkas JC, Boyer JM et al. Central vein catheter-related thrombosis in intensive care patients: incidence, risks factors, and relationship with catheter-related sepsis. Chest 1998; 114: 207–13. 6 Fratino G, Molinari AC, Mazzola C et al. Prospective study of indwelling central venous catheter-related complications in children with broviac or clampless valved catheters. J. Pediatr. Hematol. Oncol 2002; 24: 657–61. 7 Albisetti M. Thrombolytic therapy in children. Thromb. Res. 2006; 118: 95–105. 8 Albisetti M. The fibrinolytic system in children. Semin. Thromb. Hemost. 2003; 29: 339–48. 9 Journeycake JM, Buchanan GR. Thrombotic complications of central venous catheters in children. Curr. Opin. Hematol. 2003; 10: 369–74. 10 Baskin JL, Pui CH, Reiss U et al. Management of occlusion and thrombosis associated with longterm indwelling central venous catheters. Lancet 2009; 374: 159–69.
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11 Harris RP, Helfand M, Woolf SH et al. Current methods of the U.S. translating evidence into recommendations. Am. J. Prev. Med. 2001; 20 (3S): 21–35. 12 Cook R. Clinical algorithms and flow charts as representations of guideline knowledge. 2005. Available from: http://www.hinz .org.nz/journal/2005/09/Clinical-Algorithms-and-Flow-Charts-as -Representations-of-Guideline-Knowledge/923 [accessed 17 April 2012]. 13 Shiffman RN. Representation of clinical practice guidelines in conventional and augmented decision tables. J. Am. Med. Inform. Assoc. 1997; 4: 382–93. 14 Shiffman RN, Michel G, Essaihi A, Thornquist E. Bridging the guideline implementation gap: a systematic, document-centered approach to guideline implementation. J. Am. Med. Inform. Assoc. 2004; 11: 418–26. 15 Uslu S, Ozdemir H, Comert S, Bolat F, Nuhoglu A. The effect of low-dose heparin on maintaining peripherally inserted percutaneous central venous catheters in neonates. J. Perinatol. 2010; 30: 794–9. 16 Shah PS, Kalyn A, Satodia P et al. A randomized, controlled trial of heparin versus placebo infusion to prolong the usability of peripherally placed percutaneous central venous catheters (PCVCs) in neonates: the HIP (Heparin Infusion for PCVC) study. Pediatrics 2007; 119: e284–91. 17 Krafte-Jacobs B, Sivit CJ, Mejia R, Pollack MM. Catheter-related thrombosis in critically ill children: comparison of catheters with and without heparin bonding. J. Pediatr. 1995; 126: 50–4. 18 Pierce CM, 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. 19 Shah PS, Shah N. Heparin-bonded catheters for prolonging the patency of central venous catheters in children. Cochrane Database Syst. Rev. 2007; (4): CD005983. 20 Droste JC, Jeraj HA, MacDonald A, Farrington K. Stability and in vitro efficacy of antibiotic–heparin lock solutions potentially useful for treatment of central venous catheter-related sepsis. J. Antimicrob. Chemother. 2003; 51: 849–55. 21 Dillon PW, Jones GR, Bagnall-Reeb HA, Buckley JD, Wiener ES, Haase GM. Prophylactic urokinase in the management of long-term venous access devices in children: a Children’s Oncology Group study. J. Clin. Oncol. 2004; 22: 2718–23. 22 Gittins NS, Hunter-Blair YL, Matthews JN, Coulthard MG. Comparison of alteplase and heparin in maintaining the patency of paediatric central venous haemodialysis lines: a randomised controlled trial. Arch. Dis. Child. 2007; 92: 499–501. 23 Semba CP, Deitcher SR, Li X et al. Treatment of occluded central venous catheters with alteplase: results in 1064 patients. J. Vasc. Interv. Radiol. 2002; 13: 1199–205. 24 Kakzanov V, Monagle P, Chan AK. Thromboembolism in infants and children with gastrointestinal failure receiving long-term parenteral nutrition. JPEN J. Parenter. Enteral Nutr. 2008; 32: 88–93. 25 Haire WD, Deitcher SR, Mullane KM et al. Recombinant urokinase for restoration of patency in occluded central venous access devices. A double-blind, placebo-controlled trial. Thromb. Haemost. 2004; 92: 575–82. 26 Svoboda P, Barton RP, Barbarash OL et al. Recombinant urokinase is safe and effective in restoring patency to occluded central venous access devices: a multiple-center, international trial. Crit. Care Med. 2004; 32: 1990–6. 27 Jacobs BR, Haygood M, Hingl J. Recombinant tissue plasminogen activator in the treatment of central venous catheter occlusion in children. J. Pediatr. 2001; 139: 593–6. 28 Choi M, Massicotte MP, Marzinotto V, Chan AK, Holmes JL, Andrew M. The use of alteplase to restore patency of central venous lines in pediatric patients: a cohort study. J. Pediatr. 2001; 139: 152–6.
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29 Ng R, Li X, Tu T, Semba CP. Alteplase for treatment of occluded peripherally inserted central catheters: safety and efficacy in 240 patients. J. Vasc. Interv. Radiol. 2004; 15: 45–9. 30 Shen V, Li X, Murdock M, Resnansky L, McCluskey ER, Semba CP. Recombinant tissue plasminogen activator (alteplase) for restoration of function to occluded central venous catheters in pediatric patients. J. Pediatr. Hematol. Oncol 2003; 25: 38–45. 31 Monagle P, Chan AKC, Goldenberg NA et al. Antithrombotic therapy in neonates and children antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (Suppl.): e737S–e801S.
32 Eyrich H, Walton T, Macon EJ, Howe A. Alteplase versus urokinase in restoring blood flow in hemodialysis-catheter thrombosis. Am. J. Health Syst. Pharm. 2002; 59: 1437–40. 33 Deeter KH, King MA, Ridling D, Irby GL, Lynn AM, Zimmerman JL. Implementation of adapted PECARN decision rule for children with minor head injury in the pediatric emergency department. Acad Emerg Med. 2012; 19: 801–7. 34 Demmel KM, Williams L, Flesch L. Implementation of the pediatric early warning scoring system on a pediatric hematology/oncology unit. J. Pediatr. Oncol. Nurs. 2010; 27: 229–40.
Singenpoo, by Gabriel Hughes (8) from Operation Art 2011.
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Journal of Paediatrics and Child Health 50 (2014) 40–46 © 2013 The Authors Journal of Paediatrics and Child Health © 2013 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
doi:10.1111/jpc.12404
ORIGINAL ARTICLE
Prevention and treatment of intraluminal catheter thrombosis in children hospitalised in a paediatric intensive care unit Ana de Lorenzo-Pinto,1 Amelia C Sánchez-Galindo,2 Silvia Manrique-Rodríguez,1 Cecilia M Fernández-Llamazares,1 Sarah Nicole Fernández-Lafever,2 Miriam García San-Prudencio,2 Lucía Cortejoso1 and María Sanjurjo-Sáez1 1
Pharmacy Department and 2Pediatric Intensive Care Unit, Gregorio Marañón University General Hospital, Madrid, Spain
Aim: The aim of the study was to develop and implement a protocol for the prevention and treatment of catheter related intraluminal thrombosis in a paediatric intensive care unit. Methods: A computerised search was carried out on MEDLINE, through PubMed, using the medical subject heading ‘central venous catheter’, ‘central venous access device’, ‘central venous line’ associated with ‘occlusion’, ‘obstruction’, ‘catheter-related thrombosis’, ‘critically ill patients’ and ‘thrombolytic therapy’. References of reviewed articles were also searched for relevant titles as well as non-randomised controlled trials and series of cases when no information of higher level of evidence was available. Results: With the information gathered, a protocol for the prevention and treatment of catheter related intraluminal thrombosis was elaborated and those recommendations that best suit our environment were included. They were agreed upon by a broad panel of professionals working in the Pediatric Intensive Care Unit and the Pharmacy Department. Conclusions: Due to the variety of options available for the pharmacotherapeutic management of intraluminal catheter thrombosis, one measure to improve the quality of the therapy and to diminish the variability in the prescription could be the implementation of a protocol as described in this paper. Key words:
catheters; heparin; intensive care units; thrombolytic therapy.
What is already known on this topic
What this paper adds
1. Although thrombotic catheter occlusions are not a rare complication in children hospitalised at the Intensive Care Unit. 2. Their prevention and management have not been standardised. 3. Regarding pharmacologic treatments, little is known about the role of the new fibrinolytic agents, which have a high economic impact, but on the other hand, there exists a lack of strong evidence for their use.
1. The novelty of the article lies in the fact that it has been the first protocol in resolving these two aspects: standardisation and therapeutic positioning. 2. The use of fibrinolytic agents has been standardised. 3. An algorithm for both prevention and management of thrombotic catheter occlusions have been elaborated in order to reduce the complexity of the protocol, aid comprehension and facilitate successful implementation and validation.
Introduction Placement of central venous access devices (CVADs) is essential in the management of critically ill children and has tremendously improved the quality of care in these patients. Used for the administration of fluids, medications, total parenteral nutrition or blood products they may, however,
Correspondence: Dr. Ana de Lorenzo-Pinto, Pharmacy Department, Gregorio Marañón University General Hospital, C/Doctor Esquerdo 46, 28007 Madrid, Spain. Fax: +34915866621; email: ana.lorenzo@ salud.madrid.org Conflict of interest: None. Accepted for publication 23 May 2013.
40
also cause several mechanical, infectious and thrombotic complications.1 Catheter occlusion is defined as a partial or complete obstruction of the catheter limiting or preventing blood withdrawal, flushing the catheter, or administering parenteral solutions or medications.2 Thrombotic catheter occlusion accounts for 58% of all catheter occlusions and occurs when deposits of fibrin or blood within and around CVADs impede or disrupt flow through the catheter.3 It is also postulated that the localised vascular injury inflicted by the catheter induces a local prothrombotic state.4 Thrombotic catheter occlusion may delay or even interrupt infusion of therapy and may also contribute to the development of CVAD-related infections as blood clot serves as a culture medium for bacterial growth.5 Although the most commonly
Journal of Paediatrics and Child Health 50 (2014) 40–46 © 2013 The Authors Journal of Paediatrics and Child Health © 2013 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
A de Lorenzo-Pinto et al.
recognised complication of CVADs is infection,6 diagnosis of thrombotic events related to these devices is becoming increasingly prevalent.5 Thromboembolic events in children are still relatively rare compared to adults and this is one of the reasons for the lack of uniform recommendations available with regard to indications, drug of choice, route of administration and dosing regimen.7 Dose regimens have then been extrapolated from adult guidelines, but the fibrinolytic system in children is a dynamic, evolving system with unique features that markedly influence the response to thrombolytic agents.8 Besides, the pathophysiologic mechanisms of thrombosis in children are very different from those in adults. Although few clinical trials have studied prophylaxis of catheter-related thrombosis in children,9 the use of continuous heparin infusion or catheter locking solution with heparin have become a standard practice worldwide. The concentration of heparin lock solution has not been well established but literature shows a wide range of possible concentrations (10 U/mL up to 5000 U/mL). Higher doses of heparin seem to be more effective but with more side effects. Fibrinolytic agents such as urokinase and alteplase have been tested as a locking solution, but this option should be reserved for the treatment of intraluminal catheter thrombosis and not for prophylaxis purposes.10 It is of paramount importance to evaluate these drugs within the current therapeutic arsenal due to their high cost and the lack of strong evidence for their use. The aim of this study was to develop and implement a protocol for the prevention and treatment of CVADs intraluminal thrombosis in a paediatric intensive care unit (PICU).
Patients and Methods Study setting and population The study was carried out in the PICU of Gregorio Marañón University General Hospital, a Spanish academic hospital providing tertiary care for a metropolitan area of 700 000 people. The PICU comprises 11 beds and approximately 500 admissions per year. 35% of patients have cardiac disease, including postoperative care following heart surgery, 30% are post-operative patients following other surgeries and the remaining 35% are medical patients. The nurse/patient ratio is 1:1.
Catheter thrombosis
thrombosis’, ‘critically ill patients’ and ‘thrombolytic therapy’. The search was initially limited to meta-analysis, practice guidelines, randomised controlled trials and review papers performed on paediatric population up to March 2012. There were no language restrictions. References of reviewed articles were also searched for relevant titles as well as non-randomised controlled trials and series of cases when no information of higher level of evidence was available. Four investigators (1 physician and 3 pharmacists) conducted the literature search and extraction of relevant titles. The title and abstract of potentially relevant studies were screened for appropriateness before retrieval of the full article, where relevant. The initial search yielded 445 references. We eliminated 408 after initial screening because they were not related to central catheters, intraluminal thrombosis and/or pharmacological agents. The abstract or full text of the 37 remaining studies was evaluated (3 were meta-analysis, 3 were practice guidelines, 8 randomised controlled trials, 16 were review papers and 7 non randomised studies). With the information gathered, a protocol for the prevention and treatment of CVADs intraluminal thrombosis was elaborated and recommendations that best suit our environment were included. They were agreed upon by a broad panel of professionals working in the PICU and the Pharmacy Department. The protocol development process was guided by the goal of weighing evidence regarding effectiveness, tolerability, safety and cost and its adoption was intended to provide systematic guidance and structure regarding the array of potential prophylaxis and treatment options for this patient population. The level of evidence and the strength of recommendation of particular treatment options were weighed and graded according to predefined scales, as outlined in Table 1. Derivative products, such as algorithms, were elaborated in order to reduce the complexity of the protocol, aid comprehension, and facilitate successful implementation and validation.12–14 Such tools not only improve the standardisation of care, but might also help to coordinate the activities of all members working in the PICU.
Results
Study protocol
Prevention of catheter intraluminal thrombosis (Fig. 1)
CVADs definition: Catheter inserted into a central line, directly or through a peripheral access. Long-term catheters, tunnelled central venous devices or catheters with subcutaneous port systems. We performed a review of literature in order to identify the different pharmacological strategies available for the prophylaxis and the therapeutic management of catheter-related thrombosis in children, and their positioning in clinical practice. A computerised search was carried out on MEDLINE, through PubMed, using the medical subject heading (MeSH) ‘central venous catheter’, ‘vascular access devices’, ‘central venous line’ associated with ‘occlusion’, ‘obstruction’, ‘catheter-related
Prevention of CVADs intraluminal thrombosis with continuous heparin infusion: • Indication: To keep intravenous catheters patent for drug administration, hemodynamic monitoring and blood sampling. Evidence level Ib; Category of recommendation A.15,16 • Preparation instructions: Heparin solution at a concentration of 1 U/mL (add 0.5 mL of 1% heparin in 500 mL of normal saline). Prevention of CVADs intraluminal thrombosis with heparin lock solutions: • Indication: A heparin lock solution is indicated for the maintenance of catheters not being used for the administration of
Journal of Paediatrics and Child Health 50 (2014) 40–46 © 2013 The Authors Journal of Paediatrics and Child Health © 2013 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
41
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Table 1 Quality of the scientific evidence and associated grades of recommendation11 Classification of evidence levels Ia Ib IIa IIb III IV
Evidence obtained from meta-analyses of randomised controlled trials Evidence obtained from at least one randomised controlled trial Evidence obtained from at least one well-designed, non-randomised controlled study Evidence obtained from at least one well-designed, “quasi-experimental” study Evidence obtained from well-designed, non-experimental descriptive studies such as comparative studies, correlation studies, and case reports Evidence obtained from an expert committee or expert report and/or from the clinical experience of respected authorities
Categories of recommendation A B C D
Based directly on evidence level I Based directly on evidence level II or recommendation extrapolated from level I evidence Based directly in the evidence level III or recommendation extrapolated from level I or II evidence Based directly in the evidence level IV or recommendation extrapolated from level I, II, or III evidence
Grade of recommendation
Significance
A B C
Strongly recommendable (good evidence that the measure is effective and that the benefits greatly outweigh the risks) Recommendable (at least moderate evidence that the measure is effective and the benefits outweigh the risks) No recommendation for or against (at least moderate evidence of that the measure is effective, but the level of benefit is very similar to the level of risk, and a general recommendation cannot be justified) Not recommendable (at least moderate evidence that the measure is ineffective or that the risks outweigh the benefits) Insufficient, poor quality, or conflicting evidence, and the risk–benefit ratio cannot be determined
D E Quality of the evidence
Substantial net benefit
Moderate net benefit
Small net benefit
Zero or negative net benefit
Good Moderate Poor
A B E
B B E
C C E
D D E
continuous infusion fluids. Evidence level Ia; Category of recommendation A.17–19 • Preparation instructions: Heparin solution at a concentration of 20 U/mL (commercialised product). • Volume of heparin lock solution: 2 mL. This volume will be higher (3–5 mL) for locking long-term catheters (tunnelled central venous devices, catheters with subcutaneous port systems and hemofiltration catheters). • Once the catheter has been used (after completion of drug treatment or hemodyalisis therapy), it must be flushed with 5–10 mL of normal saline and then, locked with heparin solution. Before removing the syringe, the clamp must be closed to prevent blood reflux. • If the catheter needs to be used, the locking solution will have to be aspirated and discarded. Then, the catheter should be flushed again with normal saline. ■ If blood reflux into the catheter lumen occurs after the locking procedure, the catheter must be flushed with normal saline and locked again with heparin as described above. • The same heparin lock solution can be maintained up to 7 days,20 afterwards it must be renewed. Prevention of CVADs intraluminal thrombosis with fibrinolytic lock solutions: 42
• Indication: patients with prior intraluminal thrombosis. • Dosage recommendations: the fibrinolytic agent used as the locking solution should be the same as the one used for the intraluminal thrombosis resolution. – First line: urokinase 5000 U/mL. Evidence level Ib; Category of recommendation A.21 – Second line: alteplase 1 mg/mL. Evidence level Ib; Category of recommendation A.22 • Locking volume: Administer 110% of the catheter priming volume (increasing 0.1–0.2 mL of the priming volume).23 • If the catheter needs to be used, the locking solution will have to be aspirated and discarded. The catheter should be flushed again with normal saline. • Fibrinolytic lock solution should be renewed every 48–72 hours.21,22
Treatment of CVADs intraluminal thrombosis (Fig. 2) • Diagnosis: Intraluminal thrombosis should be suspected if there are signs of no-reflow or insufficient blood flow for hemodialysis. Previously, correct placement of the catheter and whether it is bent or twisted should be checked. An
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Fig. 1
• •
• • •
•
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Prevention of intraluminal catheter thrombosis.
ecography in order to exclude the presence of a blood clot inside the vessel is recommended. Treatment: 1. Flush with 5–10 mL of normal saline. If after 3 attempts the problem is not solved, administration of fibrinolytic therapy is recommended. 2. Urokinase at a concentration of 5000 U/mL. Evidence level Ib; Category of recommendation A.7,24–26 Administer 110% of the catheter priming volume (increasing 0.1–0.2 mL of the priming volume).23 Aspirate urokinase solution after 30 min and if there is not reflux, mantain for one hour. If there is no response, increase the concentration of urokinase solution to 10 000 U/mL and evaluate response at 30 and 60 min. If blood reflux into the catheter lumen occurs after the locking procedure, the locking solution will have to be aspi-
rated and discarded as well as 1–2 mL of blood, the catheter must be flushed with 5–10 mL of normal saline. 3. Alteplase at a concentration of 1 mg/mL. Evidence level III; Category of recommendation B.27–30 • Administer alteplase if treatment with urokinase fails. Administer 110% of the catheter priming volume (increasing 0.1– 0.2 mL of the priming volume).23 • Evaluate response at 30 and 60 min. • If there is no response, repeat the administration (same concentration and volume as described above). • If blood reflux into the catheter lumen occurs after the locking procedure, the locking solution will have to be aspirated and discarded as well as 1–2 mL of blood, the catheter must be flushed with 5–10 mL of normal saline. The protocol will be revised periodically as more controlled studies (level A) and new information argue for adjustment.
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Fig. 2
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Treatment of CVADs’ intraluminal thrombosis.
Discussion Catheter thrombotic occlusions and catheter-related thrombosis in critically ill children have becoming increasingly prevalent in recent years. However, the recent data are inconclusive and further research is necessary for more clearly defined guidelines 44
and recommendations with regard to both treatment and prophylaxis of catheter-related thromboembolism in paediatric patients. The novelty of the article lies in the fact that this has been the first protocol published in which antithrombotic drugs have been positioned. Clinical practice guidelines as the one
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elaborated by the American College of Chest Physicians31 have been available for the last 25 years, with the objective of health quality improvement. Most of them evaluate antithrombotic drugs and describe evidence, but therapeutic positioning is not included, a fact that may lead to a variability in the prescription of these agents. Therapeutic positioning as the described in this paper has been based on the authorised indications of use, commercial availability of the different agents, clinical experience, associated costs and patient specific characteristics, i.e., age or bleeding risk. Regarding fibrinolytic therapy, in our protocol urokinase has been positioned before alteplase due to its more costeffective profile.32 In order to evaluate implementation success, four aspects will be measured in the future: effectiveness and safety of the therapy followed in each case, medical staff adherence and satisfaction, aspects which are similar to those described by other authors.33,34 From our point of view, in order to achieve effective implementation of a protocol, the collaboration of a broad panel of health professionals working in the same direction is essential in order to promote multidisciplinary activities that ultimately result in better therapy for the patient.
Acknowledgements The authors thank Samantha Wilkinson for her invaluable help in editing the English manuscript.
References 1 Revel-Vilk S. Central venous line-related thrombosis in children. Acta Haematol. 2006; 115: 201–6. 2 Kerner JA Jr, Garcia-Careaga MG, Fisher AA, Poole RL. Treatment of catheter occlusion in pediatric patients. JPEN J. Parenter. Enteral Nutr. 2006; 30 (1 Suppl.): S73–81. 3 Stephens LC, Haire WD, Kotulak GD. Are clinical signs accurate indicators of the cause of central venous catheter occlusion? JPEN J. Parenter. Enteral Nutr. 1995; 19: 75–9. 4 Freytes CO. Thromboembolic complications related to indwelling central venous catheters in children. Curr. Opin. Oncol. 2003; 15: 289–92. 5 Timsit JF, Farkas JC, Boyer JM et al. Central vein catheter-related thrombosis in intensive care patients: incidence, risks factors, and relationship with catheter-related sepsis. Chest 1998; 114: 207–13. 6 Fratino G, Molinari AC, Mazzola C et al. Prospective study of indwelling central venous catheter-related complications in children with broviac or clampless valved catheters. J. Pediatr. Hematol. Oncol 2002; 24: 657–61. 7 Albisetti M. Thrombolytic therapy in children. Thromb. Res. 2006; 118: 95–105. 8 Albisetti M. The fibrinolytic system in children. Semin. Thromb. Hemost. 2003; 29: 339–48. 9 Journeycake JM, Buchanan GR. Thrombotic complications of central venous catheters in children. Curr. Opin. Hematol. 2003; 10: 369–74. 10 Baskin JL, Pui CH, Reiss U et al. Management of occlusion and thrombosis associated with longterm indwelling central venous catheters. Lancet 2009; 374: 159–69.
Catheter thrombosis
11 Harris RP, Helfand M, Woolf SH et al. Current methods of the U.S. translating evidence into recommendations. Am. J. Prev. Med. 2001; 20 (3S): 21–35. 12 Cook R. Clinical algorithms and flow charts as representations of guideline knowledge. 2005. Available from: http://www.hinz .org.nz/journal/2005/09/Clinical-Algorithms-and-Flow-Charts-as -Representations-of-Guideline-Knowledge/923 [accessed 17 April 2012]. 13 Shiffman RN. Representation of clinical practice guidelines in conventional and augmented decision tables. J. Am. Med. Inform. Assoc. 1997; 4: 382–93. 14 Shiffman RN, Michel G, Essaihi A, Thornquist E. Bridging the guideline implementation gap: a systematic, document-centered approach to guideline implementation. J. Am. Med. Inform. Assoc. 2004; 11: 418–26. 15 Uslu S, Ozdemir H, Comert S, Bolat F, Nuhoglu A. The effect of low-dose heparin on maintaining peripherally inserted percutaneous central venous catheters in neonates. J. Perinatol. 2010; 30: 794–9. 16 Shah PS, Kalyn A, Satodia P et al. A randomized, controlled trial of heparin versus placebo infusion to prolong the usability of peripherally placed percutaneous central venous catheters (PCVCs) in neonates: the HIP (Heparin Infusion for PCVC) study. Pediatrics 2007; 119: e284–91. 17 Krafte-Jacobs B, Sivit CJ, Mejia R, Pollack MM. Catheter-related thrombosis in critically ill children: comparison of catheters with and without heparin bonding. J. Pediatr. 1995; 126: 50–4. 18 Pierce CM, 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. 19 Shah PS, Shah N. Heparin-bonded catheters for prolonging the patency of central venous catheters in children. Cochrane Database Syst. Rev. 2007; (4): CD005983. 20 Droste JC, Jeraj HA, MacDonald A, Farrington K. Stability and in vitro efficacy of antibiotic–heparin lock solutions potentially useful for treatment of central venous catheter-related sepsis. J. Antimicrob. Chemother. 2003; 51: 849–55. 21 Dillon PW, Jones GR, Bagnall-Reeb HA, Buckley JD, Wiener ES, Haase GM. Prophylactic urokinase in the management of long-term venous access devices in children: a Children’s Oncology Group study. J. Clin. Oncol. 2004; 22: 2718–23. 22 Gittins NS, Hunter-Blair YL, Matthews JN, Coulthard MG. Comparison of alteplase and heparin in maintaining the patency of paediatric central venous haemodialysis lines: a randomised controlled trial. Arch. Dis. Child. 2007; 92: 499–501. 23 Semba CP, Deitcher SR, Li X et al. Treatment of occluded central venous catheters with alteplase: results in 1064 patients. J. Vasc. Interv. Radiol. 2002; 13: 1199–205. 24 Kakzanov V, Monagle P, Chan AK. Thromboembolism in infants and children with gastrointestinal failure receiving long-term parenteral nutrition. JPEN J. Parenter. Enteral Nutr. 2008; 32: 88–93. 25 Haire WD, Deitcher SR, Mullane KM et al. Recombinant urokinase for restoration of patency in occluded central venous access devices. A double-blind, placebo-controlled trial. Thromb. Haemost. 2004; 92: 575–82. 26 Svoboda P, Barton RP, Barbarash OL et al. Recombinant urokinase is safe and effective in restoring patency to occluded central venous access devices: a multiple-center, international trial. Crit. Care Med. 2004; 32: 1990–6. 27 Jacobs BR, Haygood M, Hingl J. Recombinant tissue plasminogen activator in the treatment of central venous catheter occlusion in children. J. Pediatr. 2001; 139: 593–6. 28 Choi M, Massicotte MP, Marzinotto V, Chan AK, Holmes JL, Andrew M. The use of alteplase to restore patency of central venous lines in pediatric patients: a cohort study. J. Pediatr. 2001; 139: 152–6.
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29 Ng R, Li X, Tu T, Semba CP. Alteplase for treatment of occluded peripherally inserted central catheters: safety and efficacy in 240 patients. J. Vasc. Interv. Radiol. 2004; 15: 45–9. 30 Shen V, Li X, Murdock M, Resnansky L, McCluskey ER, Semba CP. Recombinant tissue plasminogen activator (alteplase) for restoration of function to occluded central venous catheters in pediatric patients. J. Pediatr. Hematol. Oncol 2003; 25: 38–45. 31 Monagle P, Chan AKC, Goldenberg NA et al. Antithrombotic therapy in neonates and children antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (Suppl.): e737S–e801S.
32 Eyrich H, Walton T, Macon EJ, Howe A. Alteplase versus urokinase in restoring blood flow in hemodialysis-catheter thrombosis. Am. J. Health Syst. Pharm. 2002; 59: 1437–40. 33 Deeter KH, King MA, Ridling D, Irby GL, Lynn AM, Zimmerman JL. Implementation of adapted PECARN decision rule for children with minor head injury in the pediatric emergency department. Acad Emerg Med. 2012; 19: 801–7. 34 Demmel KM, Williams L, Flesch L. Implementation of the pediatric early warning scoring system on a pediatric hematology/oncology unit. J. Pediatr. Oncol. Nurs. 2010; 27: 229–40.
Singenpoo, by Gabriel Hughes (8) from Operation Art 2011.
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