Anticoagulation

UNFRACTIONATED HEPARIN (UFH)

Indications:

Low dose heparin infusions are used in the maintenance of central venous lines, arterial lines and the prevention and treatment of deep vein thromboses.

Administration:

Heparin can be administered by intravenous and subcutaneous routes. This protocol applies to the intravenous route only.

Heparin is compatible with 5% dextrose, 0.9% NaCl and 0.45% NaCl.

• Obtain patient weight and baseline FBC, aPTT, INR
• For maintenance of central line in infants less than 5 kg commence 10 U/kg/hr
• For shunt prophylaxis in any patient commence 10 U/kg/hr once no major postoperative bleeding
• The need for monitoring will be individualised for each patient. In general it is recommended an aPTT be obtained at 24 hours, and some stable patients may require aPTT only every 2-3 days
• Twice weekly FBC must be obtained to monitor for heparin induced thrombocytopaenia (consider HIT ELISA screen)
• Coagulation studies required for other reasons should not be obtained from a line containing heparin

Adverse events:

Bleeding whilst on low dose heparin is uncommon, but can occur. If bleeding occurs, cease heparin infusion. Check FBC, clotting and TEG. Consider seeking haematology consult.

Antidote: protamine

Precautions:

In patients with renal failure this low-dose heparin infusion may result in therapeutic anticoagulation.

Obtain venous blood sample for aPTT 4 hours post completion of loading infusion (NOT earlier). Adjust heparin infusion rate to maintain aPTT 60-85 s.

Monitoring of therapy: 

Heparin is usually monitored by aPTT. However, this may be inaccurate in certain clinical circumstances. An alternative is an anti-Xa assay.

Heparin antidote:

If anticoagulation with heparin needs to be discontinued for clinical reasons, termination of the heparin infusion will usually suffice. If an immediate effect is required, consider administering protamine sulfate.

Protamine is a medication that requires a high level of caution when being prescribed and administered. Outside cardiac surgery and ICU, consultant or fellow approval is required for the use of protamine – do not allow this to lead to delayed administration in the case of bleeding. Contact the appropriate senior person immediately.

Protamine sulfate neutralises heparin by virtue of its positive charge. Following IV administration, neutralisation occurs within 5 minutes.

The maximum dose of protamine sulfate, regardless of the amount of heparin received is 50 mg except for reversal of heparin following cardiopulmonary bypass.

Protamine sulfate is usually administered in a concentration of 10 mg/ml at a rate not to exceed 5 mg/minute. If administered too quickly, protamine sulfate may cause cardiovascular collapse (severe pulmonary hypertension).

Patients with known hypersensitivity reactions to fish, and those who have received protamine-containing insulin or previous protamine therapy may be at risk of hypersensitivity reactions to protamine sulfate.

Obtain blood for PT and aPTT 15 mins after the administration of protamine sulfate.

The dose of protamine sulfate is based on the amount of heparin received in the previous 2 hrs as follows:

LOW MOLECULAR WEIGTH HEPARIN (LMWH)

Indications:

Low molecular weight heparins are used for the prophylaxis or treatment of deep vein thrombosis. The decision to use LMWH instead of standard heparin (or warfarin) will depend upon the clinical scenario and individual patient factors such as risk of bleeding or availability of venous access.

The following are guidelines only and may need to be adapted in individual circumstances.

Administration:

• Obtain patient weight and baseline FBC, aPTT, PT.
• Dose as follows, administering via subcutaneous route, either via an insuflon catheter, or by rotating sites of subcutaneous injections.
• Timing of commencement of therapy (especially post-procedural) should be individualised.
• Duration of therapy is determined on an individualised basis, based up on indication for treatment.

Adverse events:

The major adverse event related to treatment with LMWH is bleeding.

If a patient on LMWH develops a major bleed, withhold further doses and seek an urgent haematology consult.

HIT is rare in LMWH treatment, but consider if rapid fall in platelet count.

Antidote: protamine

Precautions:

In patients with renal failure this low-dose heparin infusion may result in therapeutic anticoagulation. It is recommended that prior to any surgery or spinal or epidural procedure, 2 doses of LMWH be omitted. Haematology consult to advise on management around such procedures is advised.

Heparin antidote:

If anticoagulation with LMWH needs to be discontinued for clinical reasons, termination of the heparin infusion will usually suffice. If an immediate effect is required, consider administering protamine sulfate. Protamine is a medication that requires a high level of caution when being prescribed and administered. Outside cardiac surgery and ICU, consultant or fellow approval is required for the use of protamine – do not allow this to lead to delayed administration in the case of bleeding. Contact the appropriate senior person immediately.

Protamine sulfate neutralises heparin by virtue of its positive charge.

• If protamine is given within 8 hrs of the LMWH then a maximum neutralizing dose is 1 mg protamine/1mg (or 100U)) of LMWH given in the last dose.
• If more than 8 hours have passed since the dose of LMWH was given, administer 0.5 mg protamine per 1mg (or 100U) of LMWH given.

Protamine is administered by slow IV infusion (over 10 mins) to avoid a hypotensive reaction.

ASPIRIN

Aspirin is a medication only available for oral administration (in Australia). Tablets are available in enteric and non-enteric coating. Dispersible tablets are also available. For infants and small children it may be necessary to either crush tablets or use a dispersible tablet and administer the aspirin in liquid form. These guidelines are for the use of aspirin for its antiplatelet activity.

Indications:

Aspirin is commonly used in patients with cardiac disease and those with a history of arterial stroke. There are also certain indications for the use of aspirin in pregnancy. It is more commonly used in patients with or at risk of arterial thrombosis. There is no data to support the use of aspirin in the treatment/prevention of venous thromboembolism.

Administration and maintenance:

• Aspirin is commenced only when patients are permitted oral intake
• Commence 3-5 mg/kg/day to a maximum of 100mg
• Continue aspirin therapy as clinically indicated. For primary and secondary prophylaxis at least 3 months therapy is recommended.
• Post Norwood procedure or in patients with shunt., prophylaxis is required until surgical correction.

Therapeutic monitoring is not required!

Precautions:

A significant association between Reyes syndrome and the ingestion of aspirin by children with influenza-like illness or chicken pox has been reported in the literature.

Parents should be educated regarding the risk of developing Reyes Syndrome secondary to aspirin therapy. It should be clearly explained that aspirin therapy must be stopped in the presence of fever and/or chicken pox or measles. Paracetamol is permitted in this scenario.

The concurrent use of non-steroidal anti-inflammatory medications and aspirin is not recommended.

Mechanism:

Irreversible platelet inactivation. Once therapeutic doses are taken, antiplatelet effect remains for the lifespan of the platelet population which is 7-10 days. Patients scheduled to undergo surgical procedures should in general, stop aspirin 7-10 days prior to surgery.

Perioperative aspirin therapy may increase the risk of perioperative bleeding. The timing of cessation of aspirin therapy is the decision of the primary physician.

Adverse effects:

Patients on aspirin therapy are at a slightly increased risk of bleeding and bruising. Usually this is not significant. If a patient develops significant bleeding or bruising whilst on aspirin, prompt referral to a haematologist is required.

CLOPDIOGREL

Clopidogrel is a theinopyridine derivate that produces its antiplatelet effect through an active metabolite, which irreversibly modifies the ADP purinergic P2Y12 platelet receptor.

Indications:

Clopidogrel is widely used in adult cardiac and cardiovascular ischaemic disease (MATCH Trial), however the use in children is based on single centre experience or safety trials (PICOLO Trial)

Administration and maintenance:

• Clopidogrel is commenced only when patients are permitted oral intake
• Commence 0.2 mg/kg/day
• Continue aspirin therapy as clinically indicated. For primary and secondary prophylaxis at least 3 months therapy is recommended
• Post Norwood procedure or in patients with shunt after surgical consultation. Prophylaxis is required until surgical correction

Adverse effects:

Patients on clopidogrel therapy are at a slightly increased risk of bleeding and bruising. Usually this is not significant. If a patient develops significant bleeding or bruising whilst on clopidogrel, prompt referral to a haematologist is required

THROMBOLYSIS WITH R-TPA (ALTEPLASE)

These guidelines are for systemic thrombolytic therapy. There is no data to support the use of local thrombolytic therapy in infants and children except for line blockages.

Indications:

Massive pulmonary embolism/pulmonary embolism not responding to heparin/arterial occlusions /potential for acute, extensive DVT threatening organ or limb viability.

Contraindications:

Active bleeding/significant potential for serious local bleeding/general surgery within the previous 2 days/neurosurgery within the previous 3 weeks/AV malformations/recent severe trauma.

Preparation for infusion:

• Obtain patient weight, FBE, INR/PT, aPTT and fibrinogen. Platelet count must be 100. Fibrinogen must be >2.0. Administer FFP infusion 20 ml/kg (plus frusemide) if clinically indicated, especially in neonates <1 month (low plasminogen levels). Consider appropriate staffing requirements are in place to monitor infusion.
• Ensure adequate venous access to: infuse thrombolytic therapy and obtain blood specimens during infusion.
• Establish heparin infusion of 10 U/kg/hour to be administered continuously throughout thrombolytic infusion. If possible heparin should be administered for 6 hours prior to lysis as this may be advantageous for thrombolytic action.
• Premedicate with paracetamol and/or promethazine due to potential for allergic reactions.

Administration:

Monitoring:

• HR and BP hourly
• All puncture sites hourly during infusion and for 4 hours post infusion
• Check fibrinogen at 3 hours into infusion and at completion
• If any signs of bleeding and/or bruising occur – cease infusion, check FBC, clotting and TEG and seek urgent haematology consult
• If treating a peripheral artery thrombosis, observe limb hourly for pulse, colour, temperature and capillary return

After r-TPA: cease lytic therapy at 6 hours and increase heparin to 20 U/kg/hour aiming for aPTT 60-85 s (no bolus). Arrange clinical review (e.g. Doppler ultrasound) to determine response or need for further thrombolysis.

Complications:

In 30-50% of patients a bleeding event will occur. This is usually in the form of oozing from a wound or puncture site. Treatment with local pressure is usually sufficient. Major bleeding (intracranial, retroperitoneal, external) can develop in up to 10% of patients. If bleeding occurs, cease infusion and seek an urgent haematology consult.

Precautions:

• No IM injections during thrombolytic therapy
• Minimise patient handling during infusion
• Avoid concurrent use of warfarin and antiplatelet agents
• Delay any invasive procedures such as urinary catheterisation, resiting venous/arterial access, or perform such procedures pre-thrombolytic infusion.

BLOCKED CVL LINES

Indications: CVLs that will not infuse properly or CVLs that will not allow for the withdrawal of blood samples when this is an essential function of that line. (e.g. haemodialysis, oncology patients).

Initial Management: obtain CXR to confirm line placement and absence of kinking. Ultrasound to rule out major vessel thrombosis.

Initial action if blood related blockage:

If unable to draw blood sample, unable to infuse blood or there is blood back-up in infusion line:

• Attempt to aspirate
• Flush with 0.9% N saline
• If unsuccessful flush with strong heparin solution (100 U/ml) to a maximum of 5 ml
• Give r-tPA in each obstructed lumen: <10 kg (0.5 mg r-TPA each lumen) or >10 kg (2.0 mg r-TPA each lumen) and leave for 2-4 hrs. Try to withdraw thereafter and flush with NaCl 0.9%
• If able to flush line but no blood return, arrange diagnostic imaging as clinically indicated
• If unable to flush line obtain surgical consult or consider venography and/or ultrasound

References:

[1] CHEST 2008; 133:887S-968S: Monagle P. et al: Antithrombotic Therapy in Neonates and Children. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)

[2] CIRCULATION 2008, 117:553-559: Li et al: Dosing of Clopidogrel for Platelet Inhibition in Infants and Young Children: Primary Results of the Platelet Inhibition in Childen On cLOpridogrel (PICOLO) Trial

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