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Keywords:

  • catheters;
  • heparin;
  • intensive care units;
  • thrombolytic therapy

Abstract

  1. Top of page
  2. Abstract
  3. What is already known on this topic
  4. What this paper adds
  5. Introduction
  6. Patients and Methods
  7. Results
  8. Discussion
  9. Acknowledgements
  10. References

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.


What is already known on this topic

  1. Top of page
  2. Abstract
  3. What is already known on this topic
  4. What this paper adds
  5. Introduction
  6. Patients and Methods
  7. Results
  8. Discussion
  9. Acknowledgements
  10. References
  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.

What this paper adds

  1. Top of page
  2. Abstract
  3. What is already known on this topic
  4. What this paper adds
  5. Introduction
  6. Patients and Methods
  7. Results
  8. Discussion
  9. Acknowledgements
  10. References
  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

  1. Top of page
  2. Abstract
  3. What is already known on this topic
  4. What this paper adds
  5. Introduction
  6. Patients and Methods
  7. Results
  8. Discussion
  9. Acknowledgements
  10. References

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, 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 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

  1. Top of page
  2. Abstract
  3. What is already known on this topic
  4. What this paper adds
  5. Introduction
  6. Patients and Methods
  7. Results
  8. Discussion
  9. Acknowledgements
  10. References

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 post-operative 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.

Study protocol

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 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 pre-defined scales, as outlined in Table 1.

Table 1. Quality of the scientific evidence and associated grades of recommendation[11]
Classification of evidence levels
IaEvidence obtained from meta-analyses of randomised controlled trials
IbEvidence obtained from at least one randomised controlled trial
IIaEvidence obtained from at least one well-designed, non-randomised controlled study
IIbEvidence obtained from at least one well-designed, “quasi-experimental” study
IIIEvidence obtained from well-designed, non-experimental descriptive studies such as comparative studies, correlation studies, and case reports
IVEvidence obtained from an expert committee or expert report and/or from the clinical experience of respected authorities
Categories of recommendation
ABased directly on evidence level I
BBased directly on evidence level II or recommendation extrapolated from level I evidence
CBased directly in the evidence level III or recommendation extrapolated from level I or II evidence
DBased directly in the evidence level IV or recommendation extrapolated from level I, II, or III evidence
Grade of recommendationSignificance
AStrongly recommendable (good evidence that the measure is effective and that the benefits greatly outweigh the risks)
BRecommendable (at least moderate evidence that the measure is effective and the benefits outweigh the risks)
CNo 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)
DNot recommendable (at least moderate evidence that the measure is ineffective or that the risks outweigh the benefits)
EInsufficient, poor quality, or conflicting evidence, and the risk–benefit ratio cannot be determined
Quality of the evidenceSubstantial net benefitModerate net benefitSmall net benefitZero or negative net benefit
GoodABCD
ModerateBBCD
PoorEEEE

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

  1. Top of page
  2. Abstract
  3. What is already known on this topic
  4. What this paper adds
  5. Introduction
  6. Patients and Methods
  7. Results
  8. Discussion
  9. Acknowledgements
  10. References

Prevention of catheter intraluminal thrombosis (Fig. 1)

figure

Figure 1. Prevention of intraluminal catheter thrombosis.

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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 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:

  • 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)

figure

Figure 2. Treatment of CVADs' intraluminal thrombosis.

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  • 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 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 aspirated 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.

Discussion

  1. Top of page
  2. Abstract
  3. What is already known on this topic
  4. What this paper adds
  5. Introduction
  6. Patients and Methods
  7. Results
  8. Discussion
  9. Acknowledgements
  10. References

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 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 elaborated by the American College of Chest Physicians[31] 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 cost-effective 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

  1. Top of page
  2. Abstract
  3. What is already known on this topic
  4. What this paper adds
  5. Introduction
  6. Patients and Methods
  7. Results
  8. Discussion
  9. Acknowledgements
  10. References

The authors thank Samantha Wilkinson for her invaluable help in editing the English manuscript.

References

  1. Top of page
  2. Abstract
  3. What is already known on this topic
  4. What this paper adds
  5. Introduction
  6. Patients and Methods
  7. Results
  8. Discussion
  9. Acknowledgements
  10. References
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