Clinical Practice Guidelines

Anticoagulation Therapy Guidelines

  • Aspirin Guidelines

    Aspirin is a medication only available for oral administration. 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 or prevention of venous thromboembolism.

    Administration and Maintenance of Aspirin

    1. Aspirin is commenced only when patients are permitted oral intake.
    2. Commence Aspirin 3-5mg/kg/day to a maximum of 100mg.
    3. Continue aspirin therapy as clinically indicated. For primary and secondary prophylaxis at least 3 months therapy is recommended.

    Therapeutic monitoring is not required. Compliance may be checked using a PFA100. This test should be discussed with a haematologist prior to ordering.

    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.

    Aspirin's mechanism of action is 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. Peri-operative Aspirin therapy may increase the risk of peri-operative bleeding.

    For women taking aspirin during pregnancy, therapy is often continued until 36-38 weeks gestation. The timing of cessation of aspirin therapy is the decision of the primary physician.

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

    Aspirin should be taken after food.

    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, referral to a Haematology department is recommended.

    Local RCH Information

    Consultation with the Haematology department is available.
    Contact can be made on ext. 4891 during office hours or page the on-call Haematologist through the RCH/RWH switchboard after hours.

    For a full list of references please contact Fiona Newall on 03 9345 5827.

    Prepared by Fiona Newall (RN), Dr. Paul Monagle and Thirza Titchen (Pharm) on behalf of Womens and Childrens Health. September 2001  

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    Guidelines for the Management Blocked Central Venous Lines

    Indications

    1. CVLs that will not infuse properly.
    2. CVLs that will not allow for the withdrawal of blood samples when this is an essential function of that line. Eg. Haemodialysis, oncology patients.

    Initial management

    • obtain CXR to confirm line placement and absence of kinking.
      Blood Related Blockage Chemical Related Blockage
    Indications
    • unable to draw blood sample.
    • unable to infuse blood.
    • blood back-up in infusion line.
    • infusion running through line suddenly occludes.
    Initial Action
    1. Attempt to aspirate.
    2. Flush with 0.9% N/saline.
    3. If unsuccessful flush with strong heparin solution (100units/mL) to a maximum of 5mL.
    4. Follow tPA guidelines.
    5. If able to flush line but no blood return, arrange diagnostic imaging as clinically indicated.
    6. If unable to flush line obtain surgical consult.
    1. Attempt to aspirate.
    2. Flush with 0.9% N/saline.
    3. If unsuccessful flush with strong heparin solution (100units/mL) to a maximum of 5mL.
    4. Follow HCL guidelines.
    5. If able to flush line but no blood return, arrange diagnostic imaging as clinically indicated.
    6. If unable to flush line obtain surgical consult.

    HCL (hydrochloric acid) and tPA guidelines for local instillation

      Single lumen CVL Double lumen CVL Infusaport
    HCL 0.1M 1.5ml x 2-4 hours* 1.5ml per lumen x 2-4hrs* 1.5ml x 2-4 hrs*
    tPA
    1. < 10kg: 0.5mg tPA in 2ml*.
    2. >10kg: 2.0mg tPA in 2ml*
    (above solutions prepared by pharmacy). If unable to obtain blood return, repeatonce in 24 hours.
    1. < 10kg: 0.5mg tPA in 2ml* per lumen.
    2. >10kg: 2.0mg tPA in 2ml* per lumen.
    (above solutions prepared by pharmacy). If unable to obtain blood return, repeat once in 24 hours
    1. < 10kg: 0.5mg tPA in 3ml*
    2. >10kg: 2.0mg tPA in 3ml*
    (above solutions prepared by pharmacy). If unable to obtain blood return, repeat once in 24 hours

    * After 2-4 hours instillation of each drug, withdraw drug. If possible flush with 0.9% N/saline and attempt to aspirate blood.

    IF ABOVE ATTEMPTS DO NOT PRODUCE A FUNCTIONING CVL CONSIDER:

    Lineogram to determine: - Location of CVL's tip.

    • Potential occlusion at tip of CVL.
    • Presence of retrograde flow.
    • Potential leak.
    • Lineogram cannot rule out the presence of large vessel clot, therefore consider:

    Venography:

    1. If venography is normal and the CVL is not functioning then local occlusion must be present.
    2. If venogram is abnormal proceed to TREATMENT with heparin and warfarin or LMWH +/- warfarin.

    If venography is unavailable, perform doppler ultrasound of large vessels near and including CVL

    However, this technique is only accurate in 20% of cases in detecting large vessel thrombus of the upper venous system. Venography is the gold standard investigation for the diagnosis of large upper venous system thrombosis.

    Local RCH Information

    Consultation with the Haematology department is available.
    Contact can be made on ext. 4891 during office hours or page the on-call Haematologist through the RCH/RWH switchboard after hours.

    Urokinase is no longer available at either the Royal Women's or Children's Hospitals. All line related blockages thought to be thrombus related will now be treated with Alteplase (tPA). Streptokinase is still available in this state, however there is a substantial risk of anaphylaxis on repeat exposure. This risk is readily avoidable with the use of tPA and therefore the use of streptokinase is not recommended.

    For a full list of references please contact Fiona Newall on 03 9345 5827.

    Prepared by Fiona Newall (RN), Dr. Paul Monagle and Thirza Titchen (Pharm) on behalf of Womens and Childrens Health. September 2000 

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    Low Molecular Weight Heparin (LMWH) Guidelines

    In neonates and children, the Low Molecular Weight Heparin of choice is "Enoxaparin" (Clexane) as currently, this is the only form of LMWH available in Australia with which dose-finding studies in children have been performed. All patients requiring LMWH therapy should be referred to the Clinical Haematology Department.

    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.

    Dose Availability

     Enoxaparin

     20mg/0.2mL   (S)

     40mg/0.4mL   (S) 

     60mg/0.6mL   (G)

     80mg/0.8mL   (G)

     100mg/1.0mL (G)

     120mg/1.2mL (G)

     150mg/1.5mL (G)

    S  = dose available in pre-filled syringe
    G = graduated syringe

    Administration and Maintenance of LMWH

    1.   Weigh patient and obtain a baseline FBE. The prescribed dose should be calculated according to Table 1, depending upon the patient's age and whether LMWH is indicated for the treatment or prevention of thrombosis.

     

    Patients < 2 mths of age

    Patients 2mths-18yrs of age

    Treatment Dose

    1.5mg/kg/dose  BD

    1mg/kg/dose BD

    Prophylactic Dose

    0.75mg/kg/dose BD

    0.5mg/kg/dose BD

    Table 1. Recommended LMWH dosing for infants and children

    2.  LMWH is administered via subcutaneous route. This can be achieved by either by rotating injection sites or by injecting into an insuflonTM catheter.

    Direct subcutaneous injection should be given into a subcutaneous tissue skinfold of the abdomen or the upper-outer aspect of the thigh. The skinfold should be held throughout the injection. After removal of the needle, do not rub the site. Rather, place firm, even pressure to the site of injection for 1-5 minutes. This aids in minimizing the size of the bruise that may develop at the injection site.

    Injection via an insuflonTM cathetercan be performed in infants and children with sufficient subcutaneous tissue. Whilst there is no evidence regarding a minimum weight at which an insuflonTM catheter can be used to administer LMWH, is it advisable to avoid using insuflonTM catheters in most premature neonates and infants less than 3kg. There are reported cases of premature neonates requiring blood transfusions secondary to haemorrhaging into a subcutaneous space following the repeated injection of LMWH into an insuflonTM catheter.

    * LMWH can cause irritation of the subcutaneous tissues following injection via either method. This irritation usually passes within 5 minutes. Some children find the application of ice for 3-5 minutes prior to the injection being given minimizes this irritation.

    3.  Administration of LMWH Doses less than 10mg

    For patients prescribed doses less than 10mg, a special request can be made to pharmacy to have 10mg/0.5mL syringes prepared. These syringes are prepared by an external contractor under sterile conditions. They have a 10-day expiry from the date of preparation. A minimum of 24 hours notice is required to request these syringes via pharmacy. Families then need to be taught how to discard the unnecessary volume contained in the pre-prepared syringes.

    4.  Administration of LMWH doses between 10mg and 20mg

    For patients prescribed doses less than 20mg but greater than 10mg, the 20mg/0.2mL preparation of clexane should be used to prepare a concentration of 20mg/1.0mL.

    a) Draw 0.8mL of normal saline (0.9% NaCl) into a 2 mL syringe.
    b) Inject Enoxaprin 20mg/0.2mL directly into normal saline syringe, making a total volume of 1mL.
    c) This equals a concentration of 20mg/1mL.  
    d) From the 2mL syringe withdraw dose required with a 1mL syringe.

    5.  Administration of 20-40mg doses of LMWH

    The 20mg and 40mg pre-filled syringes are ready for immediate use and are not graduated. This means they should only be dispensed when the entire contents of that syringe equals the prescribed dose. The full contents of the syringe should be administered. When injecting directly (i.e. not via an insuflonTMcatheter), the air bubble should not be expelled to avoid loss of the drug into the syringe's dead-space. For injections into insuflonTMcatheters, the air-bubble should be expelled from the syringe to prevent repeated air instillation into site.

    6.  Preparation and administration of doses from graduated syringes

    (60mg, 80mg, 100mg, 120mg, 150mg)

    Patients to whom Clexane in graduated syringes is dispensed must be taught how to expel the unnecessary volume of drug from the syringe. The volume to be injected should be measured precisely according to the dosage recommended.

    a) Point the needle of the syringe towards the ground and gently tap the glass. An air-bubble should settle above all liquid in the syringe.
    b) Carefully depress the syringe plunger to expel excess drug until the bottom of the air-bubble is sitting level with the desired drug volume.
    c) Inject the prescribed dose into patient, ensuring the air-bubble remains behind the drug volume to be injected. This ensures no drug is 'lost' within the dead-space of the syringe. d) For injections into indwelling devices such as an insuflonTM, air should be expelled from the syringe to prevent repeated air instillation into site.

    7.  Timing of commencement of therapy (especially post-procedural) should be individualised.

    8.  Duration of therapy is determined on an individualised basis, based upon indication for treatment.

    Monitoring of LMWH therapy in infants and children

    Recent evidence demonstrates infants and children achieve highly variable dose-response to clexane. As a result, blood monitoring is vital to ensure achievement of minimum therapeutic levels and to avoid excessive anticoagulation.

    1. LMWH therapy is monitored using an anti-factor Xa assay (anti-Xa).

    2. The therapeutic range for LMWH administered to treat a thrombosis, or as bridging therapy around a procedure in patients usually prescribed oral anticoagulant therapy, is 0.5 to 1.0 units/mL.

    3. The therapeutic range for LMWH administered to prevent a thrombosis is 0.3 to 0.5 units/mL.

    4. The anti-Xa assay requires collection of a precise volume of venous or arterial blood into a coagulation (citrate) specimen collection tube. Under-filled or over-filled specimen collection tubes will produce unreliable results. If incorrectly filled specimen tubes are sent to the Core Laboratory, a request for a repeat collection will be necessary. The APTT assay will be completely normal in patients therapeutically anticoagulated with LMWH.

    5. LMWH can accumulate in the body over time, especially in infants and children. For this reason, ongoing anti-Xa measurement is essential even once the optimal LMWH dosing strategy has been determined. We recommend performing 1-2 weekly anti-Xa assays on patients who have achieved steady-state anticoagulation using LMWH and who have no significant intercurrent illnesses. For children who have an intercurrent illness and who require ongoing LMWH therapy, more frequent measurement of the anti-Xa assay may be needed. Please consult the Clinical Haematology department for advice in these situations.

    6. Nomogram for adjustment of LMWH therapy
    Table 2 outlines dose adjustments required for a given anti-Xa result in patients requiring an anti-Xa assay between 0.35 to 0.7 units/mL.

     anti-Xa level

     ? Hold Next Dose

     ? Dose Change

     ? Repeat anti-Xa level

     < 0.35 units/ml

     No

     Increase by 25%

     4 hours post next a.m. dose.

     0.35-0.49 units/ml

     No

     Increase by 10%

     4 hours post next a.m. dose.

     0.5-1.0 units/ml

     No

     No change

     1-2 weekly (if clinically stable). Collect 4 hours post an a.m. dose.

     1.1-1.5 units/ml

     No

     Decrease by 20%

     4 hours post next a.m. dose.

     1.6-2.0 units/ml

     3 hours

     Decrease by 30%

     Trough level pre next dose, then 4 hours post next a.m. dose.

     >2.0 units/ml

     Until aXa level <0.5 units/ml

     Decrease by 40%

     Trough level pre next dose and if not <0.5 units/ml repeat BD.

    Table 2. Nomogram for dose adjustment of LMWH therapy. This nomogram assumes there is no bleeding.

    Precautions

    1. Avoid the use of aspirin as this can increase the risk of bleeding.
    2. Avoid intramuscular injections and arterial punctures, if possible.

    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 Clinical Haematology consult. Rarely, LMWH therapy can cause alopecia. The extent of hair loss can vary greatly. All cases of LMWH-related alopecia have resolved upon cessation of therapy.

    LMWH Antidote

    The antidote for LMWH is Protamine sulphate. This reverses most, but not all, of the effects of LMWH. The dose of protamine sulphate given is dependent upon the dose of LMWH administered and the time of administration. If protamine is given within 8 hours of the LMWH then a maximum neutralizing dose is 1mg Protamine/100units (or 1mg) of LMWH given in the last dose.  If more than 8 hours have passed since the dose of LMWH was given, administer 0.5mg Protamine per 1mg (100units) of LMWH given. Protamine is administered by slow IV infusion (over 10 mins) to avoid a hypotensive reaction.  

    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.

    Special note regarding with-holding LMWH prior at time of procedures:
    As with other anticoagulant medications, consideration must be given to the management of LMWH prior to invasive procedures such as lumber punctures and surgery. At the Royal Children's Hospital it is recommended that prior to any spinal or epidural procedure, 2 doses of LMWH be omitted. For example, if a patient is to have a lumber puncture on Tuesday morning, they should miss their dose of LMWH the night prior to, and morning of, the lumbar puncture. Please contact the Clinical Haematology department for advice on management around such procedures.

    References

    1. Hirsh J. Low molecular weight heparins. Monograph. Decker Periodicals Inc., Hamilton, Ontario, Canada.
    2. Massicotte P, Adams M, Marzinotto V, Brooker LA and Andrew M. Low molecular weight heparin in pediatric patients with thrombotic disease: a dose finding study. J Ped 128(3): 313-318.
    3. Massicotte P. Low molecular weight heparin therapy in children. J Ped, in press.
    4. Andrew M, Massicotte P and Brooker LA. Low molecular weight heparin therapy in pediatric patients. Thrombosis in Oncology 1(2):2-5, 1998.
    5. Monagle P, Chalmers E, Chan A, deVeber G, Kirkham F, Massicotte P, et al. Antithrombotic therapy in neonates and children: American College of Chest Physicians evidence-based clinical practice guidelines (8th Edition). Chest 2008;133:887S-968S.
    6. Hull, RD. et al. Preoperative vs postoperative initiation of low-molecular weight heparin prophylaxis against venous thromboembolism in patients undergoing elective hip replacement.  Archives of Internal Medicine 159; 137-141, 1999.
    7. Checketts, MR and Wilsmith, JA. Central nerve block and thromboprophylaxis-is there a problem? (editorial) British Journal of Anaesthesia 82(2); 164-167. 1999.
    8. Yin, B. et al. Epidural haematoma after rmoval of an epidural catheter in a patient receiving high-Dose enoxaparin. British Journal of Anaesthesis 82(2):288-90. 1999.
    9. Dosing and monitoring of Enoxaparin (LMWH) therapy in children. Ignjatovic V, Najid S, Newall F, Summerhayes R, Monagle P. British Journal of Haematology. 149: 734-738.  2010
    10. The in vitro response to Low Molecular Weight Heparin (LMWH) is not age-dependent in children. Ignjatovic V, Newall F, Summerhayes R, Monagle P. Thrombosis and Haemostsis. 103: 855-856. 2010

    Produced by F. Newall, Dr. P. Monagle, B.Lilley, A. Bogovic

    June 2012.

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    Low-Dose Standard Heparin Infusion Guidelines

    Indications

    Low dose heparin infusions are used in the maintenance of central venous lines, arterial lines and the prevention of deep vein thromboses. This protocol may need to be altered according to individual patient requirements.

    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.

    1. Obtain patient weight and baseline FBE. Consider baseline APTT and PT.
    2. Dose of Heparin to be delivered to patient = 10units/kg/hr at a rate of 2mL/hour. Prepare 250 units/kg of heparin and add to dextrose or NaCl to a total of 50mls in a syringe pump.
    3. Administer heparin infusion as per clinical indications i.e. for duration of venous/arterial line, or for "at-risk" period for DVT.

    Monitoring

    1. The need for monitoring will be individualised for each patient. In general it is recommended an APTT be obtained at 24hours, and then every 2-3 days.
    2. Twice weekly FBE must be obtained to monitor for heparin induced thrombocytopaenia.
    3. 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 and seek an urgent Haematology consult. See standard Heparin infusion protocol for Protamine reversal instructions.

    Precautions

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

    Local RCH Information

    Consultation with the Haematology department is available.
    Contact can be made on ext. 4891 during office hours or page the on-call Haematologist through the RCH/RWH switchboard after hours.

    For a full list of references please contact Fiona Newall on 03 9345 5827.

    Prepared by Fiona Newall (RN), Dr. Paul Monagle and Thirza Titchen (Pharm) on behalf of Womens and Childrens Health. September 2001

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    Prophylactic Subcutaneous Standard Heparin Guidelines

    These guidelines are for the prophylactic use of subcutaneous standard heparin. It may be necessary to modify these guidelines according to individual patient requirements.

    Indications

    1. Patients undergoing major surgery where there is the likelihood for long periods of inactivity.
    2. Patients who have experienced major trauma and who are expected to be immobilized for an extended period of time.

    Administration and Monitoring

    These guidelines are for adult patients only. It is highly recommended that a Haematology consult be obtained prior to the institution of prophylacitc anticoagulation in children.

    1. Obtain baseline FBE, APTT, PT to exclude the presence of an underlying coagulation disorder.
    2. Administer 5000units of standard heparin per 0.2mL subcutaneously twice daily via rotating injection sites.
    3. Monitoring of the APTT is not necessary, however, a platelet count should be checked after 3-4 days of therapy to monitor for the development of heparin induced thrombocytopaenia.

    Precautions

    In patients with renal failure prophylactic heparin injections may result in therapeutic anticoagulation.

    As with other anticoagulant medications, consideration must be given to the management of prophylactic heparin injections prior to invasive procedures such as lumber punctures and surgery.

    Concurrent use of non-steroidal anti-inflammatories (NSAIDs) eg. Aspirin /voltaren, should NOT be allowed in patients receiving subcutaneous heparin and who have an epidural insitu. For patients with a history of coagulation disorders or peri-operative anticoagulant therapy a Haematology consult is strongly advised.

    Adverse Events

    Bleeding related to prophylactic standard heparin is uncommon but can occur. If a patient on heparin develops bleeding, cease heparin injections and seek urgent Haematology consult. See the Therapeutic Standard Heparin Infusion protocol for heparin reversal guidelines with protamine.

    Local RCH Information

    Consultation with the Haematology department is available.
    Contact can be made on ext. 4891 during office hours or page the on-call Haematologist through the RCH/RWH switchboard after hours.

    For a full list of references please contact Fiona Newall on 03 9345 5827.
    Prepared by Fiona Newall (RN), Dr. Paul Monagle and Thirza Titchen (Pharm) on behalf of Womens and Childrens Health. September 2001

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    Systemic Lytic Therapy Guidelines

    These guidelines are for systemic lytic therapy. There is no data to support the use of local lytic therapy in infants and children except for line blockages (see protocol for management of CVL blockages).

    Indications

    1. Massive pulmonary embolism
    2. Pulmonary embolism not responding to heparin
    3. Arterial occlusions
    4. Potential for acute, extensive DVT threatening organ or limb viability.

    Contraindications

    1. Active bleeding
    2. Significant potential for serious local bleeding
    3. General surgery within the previous 10 days
    4. Neurosurgery within the previous 3 weeks
    5. AV malformations
    6. Recent severe trauma.

    Preparation for infusion

    1. Obtain patient weight, FBE, INR/PT, APTT and fibrinogen. Platelet count must be >100. Fibrinogen must be ᄈ 2.0. 
      Administer FFP infusion 20ml/kg if clinically indicated.
    2. Consider appropriate staffing requirements are in place to monitor infusion.
    3. Ensure adequate venous access to: 
          a). infuse lytic therapy, and
          b). obtain blood specimens during infusion.
    4. Establish heparin infusion of 10units/kg/hour to be administered continuously throughout lytic infusion. If possible heparin should be administered for 6hours prior to lysis as this may be advantageous.
    5. Streptokinase vs. Alteplase?

      Streptokinase

      Alteplase

      1. Patient older than 1 year of age.
      2. No previous exposure to streptokinase.
      1. Patient less than 1 year of age.
      2. Previous exposure to streptokinase.
      3. Severe life or limb threatening clot.
      4. Known recent streptococcus infection.

      DO NOT use Streptokinase if used previously in the same patient.

      Premedicate with Paracetamol and/or promethazine due to potential for allergic reactions.

      Administer Lytic therapy as per following guidelines:

        Loading dose Infusion dose Maximum loading dose
      Streptokinase 2000 units/kg over 10 minutes 1000 units/kg/hour over 6 hours 250,000 units
      TPA No 0.5mg/kg/hour over 6 hours. n/a
    6. Throughout infusion monitor: - pulse & BP hourly.
    • All puncture sites hourly during infusion and for 4 hours post infusion.
    • Check Fibrinogen 3 hours into infusion and at completion.
    • If any signs of bleeding and/or bruising occur cease infusion and seek urgent Haematology consult.
    • If treating a peripheral artery thrombosis, observe limb hourly for pulse, colour, temperature and capillary return.

    Cease lytic therapy at 6 hours. Increase heparin to 20units/kg/hour (no bolus). Arrange clinical review to determine response or need for further lysis.

    Complications of Thrombolytic therapy

    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, retroperitoeal, external) can develop in up to 10% of patients. If bleeding occurs, cease infusion and seek an urgent Haematology consult.

    Precautions

    1. No IM injections during lytic therapy.
    2. Minimize patient handling during infusion.
    3. Avoid concurrent use of warfarin and antiplatelet agents.
    4. Delay any invasive procedures such as urinary catheterization, re-siting venous/arterial access, or perform such procedures pre-lytic infusion.

    Local RCH Information

    Consultation with the Haematology department is available.
    Contact can be made on ext. 4891 during office hours or page the on-call Haematologist through the RCH/RWH switchboard after hours.

    Urokinase is no longer available at either the Royal Womens or Childrens Hospitals. Streptokinase is still available in this state, however there is a substantial risk of anaphylaxis on repeat exposure. This risk is readily avoidable with the use of tPA and therefore the use of streptokinase is not recommended.

    For a full list of references please contact Fiona Newall on 03 9345 5827.

    Prepared by Fiona Newall (RN), Dr. Paul Monagle and Thirza Titchen (Pharm) on behalf of Womens and Childrens Health. September 2001

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    Therapeutic Standard Heparin Infusion Guidelines

    These guidelines are for the treatment of deep vein thrombosis and/or pulmonary embolus.

    The following are guidelines for the commencement and maintenance of Heparin infusions. It may be necessary to modify this protocol according to individual patient requirements.

    Administration

    Heparin can be administered by intravenous or subcutaneous routes. This protocol applies to the intravenous route only. Heparin is compatible with 5% Dextrose and 0.9% NaCl.

    1. Obtain baseline FBE, APTT and PT.
    2. Any patient with a low platelet count or an abnormal APTT or PT should be discussed with a haematologist prior to starting heparin.
    3. Obtain the patients weight.

      The solution for maintenance unfractionated heparin therapy such that 1mL/hour = 10U/kg/hr can be prepared as follows:

                  Weight (kg) X 10 X volume of solution (e.g. 50 mL)  = units of heparin in that volume of solution

      For example, a child weighing 15 kg:

                  15 X 10 X 50 = 7,500 U in 50 mL

      This gives 150 U/mL and therefore, 1mL/hr = 10 U/kg/hr

      Patients who are fluid restricted may receive more concentrated heparin solutions; however, increased vigilance is required:

                  Weight (kg) X desired rate (U/kg/hr) for 1mL/hr

      infusion X volume of solution (mL).

      For example, a child weighing 15kg with a desire to give 20U/kg/hr in 1mL

                  15 X 20 X 50 = 15,000 U in 50mL

      This gives 300 U/mL and therefore 1mL/hr = 20 U/kg/hr. 

    4. Recommended loading and initial maintenance doses:

        <1 year<1 year >1 year Adult
      Loading dose 75units/kg 75units/kg 5000units
      Maintenance 25units/kg/hr 20units/kg/hr 30ml/hr (of 50units/mL)
    5. * loading dose to be infused over 10 minutes.

      Patients with renal failure will require modified doses.

    6. Obtain venous blood sample for APTT 4 hours post completion of loading infusion (NO earlier). Adjust heparin infusion rate to maintain APTT 2.5 x the baseline APTT or within the range determined as optimal for that patient.

    Nomogram for Adjusting Heparin Dose

    APTT
    (seconds)
    BOLUS
    (units/kg)
    HOLD
    (minutes)
    RATE CHANGE
    (units/hr)
    REPEAT APTT
    < 50 50 0 Increase 20% 4 hours
    50-59 0 0 Increase 10% 4 hours
    60-85 0 0 No change 24 hours
    86-95 0 0 Reduce 10% 4 hours
    96-120 0 30 Reduce 10% 4 hours
    > 120 0 60 Reduce 15% 4 hours

    * The rate changes suggested in the table above are to be calculated as a percentage of the total infusion, that is, in units/hour NOT mLs/hour.

    * Heparin infusion orders should include both units/kg/hour delivered (children) or units/hour (adults) and the corresponding mL/hour rate.

    * Patients should have a dedicated line for heparin infusions. The infusion must not be stopped or interrupted for other medication. APTT blood samples can NOT be drawn from the same line.

    Monitoring of Therapy

    1. Heparin is usually monitored by APTT. However, this may be inaccurate in certain clinical circumstances. An alternative is an anti Xa assay. Haematology consult is recommended if there are any concerns.
    2. Therapeutic range for standard heparin using APTTs corresponds to an anti Xa assay of 0.3-0.7units/mL APTT results across laboratories cannot be reliably compared.
    3. APTT blood samples can NOT be drawn from the same line as the heparin infusion. Coagulation tubes must be filled exactly to the specified mark to avoid erroneous results.
    4. Twice weekly FBEs, (platelet count) are required. If there is an abrupt decrease in platelet count, (eg 50%) consider Heparin Induced Thrombocytopaenia (HIT) and arrange immediate Haematology consult.
    5. Avoid IM injections and arterial stabs during anticoagulant therapy. When such procedures are clinically necessary, ensure adequate external pressure is applied post-procedure.
    6. The duration of heparin therapy is dependant upon the primary problem. Please consult the Haematology department for guidelines.
    7. Avoid aspirin and other anti-platelet medications during heparin therapy.

    Adverse Events

    The major adverse event potentially related to standard heparin infusion is bleeding. If a patient on heparin develops bleeding, cease heparin infusion and seek urgent Haematology consult.

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

     Time since Last Heparin Dose    Protamine Dose (mg) per 100units Heparin received  
    < 30 min 1 mg
    30-60 min 0.5-0.75 mg
    60-120 min 0.375-0.5 mg
    > 120 min 0.25-0.375 mg

    The maximum dose of protamine sulfate, regardless of the amount of heparin received is 50mg except for reversal of heparin following cardiopulmonary bypass. Protamine sulfate is usually administered in a concentration of 10mg/mL at a rate not to exceed 5mg/minute. If administered too quickly, protamine sulfate may cause cardiovascular collapse. 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 min after the administration of protamine sulfate.

    Local RCH Information

    Consultation with the Haematology department is available.  
    Contact can be made on ext. 4891 during office hours or page the on-call Haematologist through the RCH/RWH switchboard after hours.

    For a full list of references please contact Fiona Newall on 03 9345 5827.

    Prepared by Fiona Newall (RN), Dr. Paul Monagle and Thirza Titchen (Pharm) on behalf of Womens and Childrens Health. September 2001

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    Warfarin Guidelines

    Warfarin is the generic name for the most commonly used oral anticoagulant of which there are 2 brands.
    It is not advisable to use different brands interchangeably.

    Both brands of warfarin colour-code their tablets. The following table describes the availability of tablet strengths and their corresponding colour.

      1mg 2mg 3mg 5mg
    Coumadin Light tan Lavender n/a Green
    Marevan Brown N/a Blue Pink

    The following are guidelines only and may be modified according to individual requirements.

    Guidelines

    1. Most patients require 3-5 days of warfarin before achieving a stable maintenance phase.
    2. If the patient is receiving TPN, removal of Vitamin K from Nutrient solution may be necessary
    3. for infants, consideration must be given to formula vs breast fed babies. For babies exclusively breast fed, supplementing feeds with one formula feed/day to provide a constant intake of Vitamin K may be required.
    4. Target INR for Clinical Indication

      Target INR Range

        Target Target Range
      Deep Vein Thrombosis/P.E.  2.5 2.0-3.0
      Mechanical Valves 3.0 2.5-3.5
      Post-Fontan surgery 2.5 2.0-3.0
      CVL clot prophylaxis 1.5 1.2-2.0
      Cardiomyopathy 2.5 2.0-3.0
      Ischaemic stroke 2.0 1.5-2.5

      Before altering a patient's warfarin dose be sure you know what INR you are aiming for!

    5. If the patient is receiving other medications (eg. antibiotics) the loading dose may need to be adjusted accordingly.

    6. Active warfarin is NOT evenly distributed within each tablet. As such, doses should be given in whole tablet sizes. Many patients will require alternate day doses or dose reduction. e.g. alternating 3 and 4mg daily, instead of 3.5mg daily.

    Loading Dose - Day 1

    Administer 0.2mg/kg orally as a single nocte dose, up to a maximum 5mg. (For patients with liver dysfunction or severe renal impairment reduce this to 0.1mg/kg to a maximum of 5mg). For adult patients commencing warfarin begin with a loading dose of 5mg.

    Loading Dose - Day 2 to 4

    Subsequent loading doses are based on individual INR response.
    The dose reductions in table below are critical to avoid "over-shooting" the target range.

    INR Warfarin Adjustment
    1.1-1.3 Repeat initial loading dose
    1.4-1.9 50% of initial loading dose
    2.0-3.0 50% of initial loading dose
    3.1-3.5 25% of initial loading dose
    >3.5 Hold until INR <3.5 then restartAt 50% less than previous dose.

    If the INR is not > 1.5 on Day 4, the patient should be reassessed and the loading dose per kg increased based on the individual clinical need.

    Warfarin Maintenance Guidelines

    Warfarin management is complex and affected by numerous factors. Management should be performed by someone experienced in warfarin dosing.

    Thorough patient education is the key to successful management of patients on oral anticoagulants.

    Outpatient Follow-Up

    1. Heparin can be ceased when the INR is therapeutic for 2 consecutive days.
    2. Monitor INR within 3 days of discharge, or as directed by Haematology department.
    3. Always check an INR within 5 days of a dose change.
    4. As patients are stable on a given dose of warfarin, the interval between testing INRs can be lengthened. INRs should be monitored at least once a month.
    5. Duration of therapy is dependent upon the indication for anticoagulation.

    NB: warfarin is teratogenic in early pregnancy and reliable birth control is recommended. All patients of child bearing age should discuss contraception and pregnancy with a Haematologist before commencing warfarin. Warfarin is safe during breast-feeding.

    Warfarin Interactions

    It must be assumed that all medications will influence the individual's response to warfarin.

    Adverse Events

    The major adverse event associated with warfarin is bleeding. If a patient on warfarin bleeds, withhold any further doses, and seek urgent Haematology consult.

    Warfarin Reversal

    Vitamin K is used to reverse the effects of warfarin. The dose to be administered and the indications for concurrent FFP or prothrombin concentrate are clinically driven. The following are guidelines only.

    No Bleeding

    1. rapid reversal is needed and the patient WILL require warfarin again in the near future:

      Administer Vitamin K 0.5 to 2.0 mg subcut or orally (NOT intramuscularly) according to patient's size.

    2. rapid reversal is needed and the patient will NOT require warfarin again:

    Administer Vitamin K 2-5mg subcut. (not IM).

    Significant Bleeding

    1. Significant but not life-threatening bleeding: Administer Vitamin K 0.5mg to 2mg Subcut. Plus FFP (20mL/kg I.V.) to a maximum of 4 units.

      Administer Vitamin K 0.5mg to 2mg subcut. plus FFP (20ml/kg I.V.) to a maximum of 4 bags.

    2. Significant bleeding that IS Li