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Ahmed, Hafeez, Khan, AlKamali, Ghayb, and Madasu: Treatment of peripherally inserted central catheter line-associated thrombus in a preterm neonate with low-molecular-weight heparin

Introduction

Vascular catheters are considered ‘lifelines’, indispensible in neonatal intensive care units (NICUs). Insertion of an intravascular catheter is the most common invasive procedure in the NICU.1 The peripherally inserted central catheter (PICC) offers several advantages over other devices used to provide central vascular access in neonates. A neonatal PICC can be inserted at the patient’s bedside with the use of an analgesic agent and radiographic verification, and it can remain in place for several weeks or months. The small diameter of its lumen is ideal for the extremely small neonate.2 In sick neonates, peripherally placed percutaneous central venous catheters are used to provide long-term vascular access.3

Major complications associated with these catheters include mechanical complications (catheter thrombosis, occlusion or dislodgement) and infection.3 The use of central lines is the main cause of thrombosis in neonates.4

Thrombotic complications are thought to arise by several mechanisms: (1) damage to the vessel wall by the catheter or by substances infused through the catheter [e.g. total parenteral nutrition (TPN)]; (2) disrupted blood flow; or (3) thrombogenic catheter materials.4 It is reported that approximately 2.4 out of 1000 of newborns admitted to NICUs experience a symptomatic thromboembolic event (TE), 89% of which are related to the use of a central venous line.5

Neonatal thrombosis is diagnosed fairly rarely. With the exception of spontaneous renal venous thrombosis, almost all cases are associated with indwelling catheters. Doppler ultrasound techniques are the most popular means of confirming the diagnosis.5

Most neonates with thrombosis are asymptomatic, and TEs, which are often related to indwelling catheters, may be detected coincidentally during routine ultrasound examination.6 Although the haemostatic system of the term-born and preterm neonate is significantly different from that of children and adults, most authors refer to the haemostatic potential of the ‘healthy’ neonate as being balanced, promoting neither haemorrhage nor thrombosis.7

The vitamin K-dependent coagulation factors (II, VII, IX and X) and the components of the contact system (factors FXI and FXII, prekallikrein and high-molecular-weight kininogen) show significantly reduced plasma activities in neonates compared with children and adults. However, the vitamin K-dependent inhibitors of coagulation, protein C and protein S, are also reduced in the neonatal period, counterbalancing the reduced clotting potential of neonatal plasma. Neonatal platelets have been reported to be hyporeactive; however, this deficiency seems to be balanced by increased von Willebrand factor activity, resulting in overall normal platelet function. The activity of the fibrinolytic system in the newborn is reduced compared with that of adults and older children as a result of both decreased plasma activity of plasminogen and increased plasma levels of plasminogen activator inhibitor, which may explain the high rate of TEs associated with intravascular devices in newborns; however, to date there is no evidence that the neonatal haemostatic system either protects against or promotes thrombus formation.7

Critical illness is a well-recognized risk factor for TEs in all age groups. Immobilization, rapid changes in intravascular volume and extensive intravascular instrumentation contribute to the enhanced risk of venous and arterial thrombosis in patients in intensive care units. In neonates, this risk is further increased by the fact that indwelling catheters are larger than the diameter of the vessel, in most cases obstructing approximately 50% of the lumen. Hence, it is not surprising that almost 90% of TEs in neonates are caused by intravascular devices. Additional risk factors include, but are not limited to, sepsis, asphyxia, maternal diabetes, poor cardiac output and dehydration. Neonates are born with a high haematocrit level and there is a tendency for their intravascular volume to contract within the first days of life, making them even more prone to TEs.7

Despite the limited evidence on the safety and efficacy of anticoagulant treatment in preterm neonates, low-molecular-weight heparin (LMWH) is increasingly advocated for numerous clinical indications.6 The LMWHs are derived from unfractionated heparin but have a shorter polysaccharide chain length. Therefore, they differ in their action from heparin by having a more profound effect on factor Xa than on thrombin.8 The ratio of the anti-Xa to thrombin varies from 1.5 to > 10.13; in addition, LMWH has more stable pharmacokinetics and, thus, a more predictable clinical response than heparin. For relatively stable infants, such as those with catheter-related thrombosis who are not critically ill, the subcutaneous route is an advantage, as is the more stable pharmacokinetics, which leads to stable dosing and a reduced requirement for laboratory monitoring.8

Case history

A baby girl was born by a lower uterine segment caesarean section to a mother with parity 2 and no history of abortions at 27 weeks’ gestation. The Apgar score was 6 and 9 at 1 and 5 minutes, respectively. She had respiratory distress and required ventilation and one dose of surfactant. TPN was started on day 1 through an umbilical venous catheter. The umbilical venous catheter was removed on day 7 in accordance with our unit’s protocol and a PICC line inserted in the right upper limb and TPN continued with 0.5 units of heparin per ml of TPN added. On day 7 of life, the baby’s condition deteriorated and she was screened for sepsis. She tested positive for C-reactive protein (CRP) and her blood culture grew coagulase-negative Staphylococcus. Her sepsis resolved with intravenous (i.v.) antibiotics.

A systolic murmur was detected on day 13 of life. Echocardiography revealed a patent ductus arteriosus of 1.5 mm and a thrombus at the right atrium that was 10 mm long and 5.6 mm wide (Figures 1 and 2), attached mainly to the PICC line. The baby was investigated and treated.

FIGURE 1

Subcostal view showing a large homogeneous mass (thrombus) protruding from SVC–right atrial junction and filling almost half of the right atrial cavity.

HMJ-635-fig1.jpg
FIGURE 2

Subcostal view showing a small elongated mass (thrombus).

HMJ-635-fig2.jpg

Investigations

The investigations undertaken included:

  • a full blood count (Table 1)

  • CRP, which was 127 mg/l; a repeat CRP test was negative

  • blood culture, which showed coagulase-negative Staphylococcus

  • a repeat blood culture showed no growth

  • prothrombin time (12.5 seconds), activated partial thromboplastin time (55 seconds) and the international normalized ratio (1.2)

  • fibrinogen, which was 222.8 mg/dl (normal levels are 200–400 mg/dl)

  • D-dimer levels, which were high at 4.23 mg/l (normal levels are 0.1–0.5 mg/dl)

  • no detectable factor V gene mutation

  • protein S level, which was normal at 61%

  • protein C and antithrombin III levels, which were slightly low at 30% and 46%, respectively

  • factor X assay, which was normal (82.1%).

TABLE 1

Full blood count

Description At birth Day 14
White blood cell count (cells/μl) 8600 7700
Haemoglobin (g/dl) 19.8 10
Haematocrit (%) 58.7 29.4
Platelets (cells/μl) 125 000 12 000
Reticulocyte count (%) 6.5

Treatment

The PICC line was not removed for fear of displacing the thrombus. The baby was treated with LMWH at a dose of 1.5 mg/kg subcutaneously twice a day after checking the baseline haematological parameters. Brain ultrasonography was also completed before starting the treatment. This showed only bilateral periventricular flare – there was no evidence of any bleeding.

A full blood count and renal function test were performed weekly and were within the normal range. Brain ultrasonography was also repeated weekly and was normal before discharge. Echocardiography was repeated after 1 week of treatment and showed the right atrial thrombus to be significantly smaller in size (6 × 1.5 mm compared with 10 × 5.6 mm in the previous echocardiogram).

The right atrial thrombus resolved after 2 weeks of treatment (Figure 3). The PICC line was removed after resolution of the thrombus. LMWH was continued for a total of 3 weeks. Echocardiography was repeated 1 week after stopping LMWH and follow-up echocardiography was performeed after 2 months. There was a 4-mm atrial septal defect with left-to-right shunt, with a slightly dilated right atrium and right ventricle. There was no evidence of any recurrent thrombus (Figure 4). She is regularly followed up in the neonatology and paediatric cardiology clinic. Her growth parameters and development are normal and there is no evidence of any thrombus formation.

FIGURE 3

Four-chamber view on colour Doppler echocardiography showing no right atrial mass and a small secundum atrial septal defect.

HMJ-635-fig3.jpg
FIGURE 4

Modified four-chamber view showing secundum atrial septal defect and no mass or thrombus in the right atrium.

HMJ-635-fig4.jpg

Discussion

Our baby, born preterm, required a PICC line for i.v. fluid and medication administration.

The use of PICCs in modern medical practice has increased rapidly for several reasons, including ease of insertion, the fact that PICCs have various different uses (e.g. drug administration and venous access) and their perceived safety and cost-effectiveness compared with other central venous catheters.9 A coincidental thrombus was identified when echocardiography was performed because of a systolic murmur. PICCs are associated with a number of significant complications, including mechanical complications, infection and thrombosis.10

The use of heparin in the fluid infused through the PICC line helps prevent occlusion of the line, but does not prevent thrombus formation.4 Suspicion or confirmation of a venous thrombus warrants prompt catheter removal; however, owing to the risk of emboli, current recommendations are to delay central venous catheter removal if a thrombus has been detected until 3–5 days after anticoagulant therapy has been given, although no clinical studies exist to support this practice.10 Therefore, the removal of the PICC line was delayed considering the risk of possible emboli.

Because of the risk of the thrombus extending and becoming dislodged, the baby was treated with LMWH. LMWH was used because of its advantages. These include greater bioavailability when given by subcutaneous injection, longer duration of anticoagulant effect and clearance that is independent of dose, which results in a more predictable response. It can be administered subcutaneously and requires minimal laboratory monitoring and dose adjustment; these are important considerations in newborns with poor venous access. Potential advantages are the reduced risk of immune-mediated thrombocytopenia and osteoporosis.11

The right atrial thrombus resolved after treatment with LMWH, and there was no evidence of any bleeding tendency during the treatment. The baby, on follow-up, was growing well and was developmentally normal and there was no recurrence of the thrombus.

References

1. 

Ramasethu J. Complications of vascular catheters in the neonatal care unit. Clin Perinatol 2008; 35:199–222. http://dx.doi.org/10.1016/j.clp.2007.11.007

2. 

McCay AS, Elliott EC, Walden M. PICC placement in the neonate. N Engl J Med 2014; 370:e17. http://dx.doi.org/10.1056/NEJMvcm1101914

3. 

Shah PS, Shah VS. Continuous heparin infusion to prevent thrombosis and catheter occlusion in neonates with peripherally placed percutaneous central venous catheters. Cochrane Database Syst Rev 2005; 3:CD002772. http://dx.doi.org/10.1002/14651858.cd002772.pub2

4. 

Revel-Vilk S, Ergaz Z. Diagnosis and management of central-line-associated thrombosis in newborns and infants. Semin Fetal Neonatal Med 2011; 16:340–4. http://dx.doi.org/10.1016/j.siny.2011.07.003

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Schmidt B, Andrew M. Neonatal thrombosis: report of a prospective Canadian and international registry. Pediatrics 1995; 96:939–43.

6. 

Van Elteren HA, Veldt HS, te Pas AB, et al. Management and outcome in 32 neonates with thrombotic events. Int J Pediatr 2011; 2011:1–5. http://dx.doi.org/10.1155/2011/217564

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Veldman A, Nold MF, Michel-Behnke I. Thrombosis in the critically ill neonate: incidence, diagnosis, and management. Vasc Health Risk Manag 2008; 4:1337–48.

8. 

Young G. Old and new antithrombotic drugs in neonates and infants. Semin Fetal Neonatal Med 2011; 16:349–54. http://dx.doi.org/10.1016/j.siny.2011.07.002

9. 

Chopra V, Anand S, Hickner A, et al. Risk of venous thromboembolism associated with peripherally inserted central catheters: a systematic review and meta-analysis. Lancet 2013; 382:311–25. http://dx.doi.org/10.1016/S0140-6736(13)60592-9

10. 

Saxonhouse MA. Management of neonatal thrombosis. Clin Perinatol 2012; 39:191–208. http://dx.doi.org/10.1016/j.clp.2011.12.018

11. 

Chan AKC. Management of Thrombosis in the Newborn. 2015. URL: www.uptodate.com/contents/management-of-thrombosis-in-the-newborn?source=search_result&search=Management+of+thrombosis+in+the+newborn&selectedTitle=1%7E17 (accessed 21 March 2016).




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