This page contains Clinical Practice Guidelines for the administration of Standard Heparin infusions, systemic lytic therapy and the management of a blocked central venous access device. 
In addition, the Clinical Haematology department has developed guidelines to support clinician’s management of warfarin and low molecular weight heparin (Clexane). These can be accessed from the department’s webpage, or via the links below

Unfractionated Heparin (UFH)

The following are guidelines for the commencement and maintenance of Unfractionated Heparin (UFH) infusions, also known as Standard Heparin. It may be necessary to modify this protocol according to individual patient requirements. Outside of Rosella and Koala, the Clinical Haematology Department should be consulted before commencing a UFH infusion

Prescribing and administering UFH

At RCH we only administer UFH by intravenous route. This guideline applies to the intravenous route only. UFH is compatible with 5% Dextrose and 0.9% NaCl

Intravenous orders for UFH must state ALL of the following:

1. Total Dose (in units) of UFH in a prepared syringe. No abbreviation for units will be accepted
2. Dose (in units) to be infused per kilogram per hour (eg 20 units/kg/hour)
3. Volume (mL) to be infused per hour.
4. Individualised Target APTT range
   1. Obtain baseline FBE, APTT, INR, Creatinine and renal function.
   2. Any patient with a low platelet count or an abnormal APTT or INR should be discussed with a Haematologist prior to starting UFH.
   3. Three concentrations of UFH infusions are used across RCH:
5. 1000 units in 50 mL (for patients <10 kg)
6. 5000 units in 50 mL (for patients >10 kg and <40 kg)
7. 10,000 units in 50 mL (for patients >40 kg)

NB Patients that are fluid restricted may require more concentrated UFH solutions than that recommended based on weight. If this is necessary, increased vigilance is required and a Clinical Haematology consult is highly recommended.

4. Preparing an UFH syringe or bag
   1. IV orders should state the total dose (units), dose to be administered (units per kilogram per hour) and the volume (mL per hour) to be infused. If any of these details are missing, the prescribing doctor needs to rechart the order

                b.   Draw up required units of heparin and volume of diluent  

5. Recommended therapeutic doses.  Patients with renal failure will require modified doses and should be discussed with Clinical Haematology. 

Table 1. Recommended age-related UFH dose to commence therapeutic anticoagulation 

6. Bolus doses of UFH on commencement of therapy are NOT recommended unless specifically requested by the Clinical Haematology team
7. Patients should have a dedicated line for UFH infusions. The infusion should not be

       stopped or interrupted for other medication.

8. Due to the significant risk for errors in drug calculation, infusion preparation and  

       programing infusion pumps when commencing UFH infusions, careful checking

       procedures are required, including double checking at the patient bedside.
 

9.   Flow rate (mL per hour) will vary according to weight.

Figure 1. UFH flow rate calculation

The table below provides examples of UFH calculations based upon patient weight. All dose calculations are based upon age-appropriate UFH units/kg recommended to achieve therapeutic anticoagulation.  

Table 2. Examples of UFH infusion calculations based on weight and units/kg/hr required

*maximum upper limit of 1500 units per hour starting dose breached by weight x 18 unit/kg/hr calculation

Monitoring therapeutic UFH infusions

UFH is monitored using the APTT assay. The table below summarises a UFH dosing nomogram based on the APTT result. APTT results across laboratories cannot be reliably compared.

In some clinical scenarios, the APTT may not be accurate, and an anti-Xa assay may be used. Within adult based studies, an anti-Xa assay of 0.35-0.7 units/mL equates to a therapeutic UFH dose. Consultation with the Clinical Haematology unit is recommended in such scenarios.

1. Obtain venous blood sample for an APTT assay 6 hours post UFH commencement, or as directed by the Clinical Haematology department. In most instances, it is not necessary to wake patients overnight for UFH monitoring tests. This checking of the APTT is to ensure patients are not supra-therapeutic. A UFH dose change may not be required.
2. Adjust UFH infusion rate to maintain APTT within the range determined as optimal for that patient according to the Nomogram below. Clinical Haematology consultation is recommended to determine ongoing monitoring requirements. For most patients one APTT assay every 24 hours is sufficient.

If two unsuccessful attempts to obtain a venous APTT have occurred, contact the Clinical Haematology department before further attempts are made. 

Table 3. Nomogram for adjusting UFH dose

*Bolus may be appropriate depending on clinical situation and perceived bleeding risk. Consult the Clinical Haematology department.  

3. The rate changes suggested in the table above are to be calculated as a percentage of 

       the total infusion, that is, in units/kg/hour.

4. Do NOT turn off UFH infusion prior to collecting an APTT or anti-Xa assay.

5. APTT blood samples should NOT be drawn from the same line (or limb) as the UFH

    infusion. If this cannot be avoided, a minimum discard volume of 5 mL should be collected

    prior to collecting the APTT or Anti-Xa sample.

6.  Coagulation tubes must be filled exactly to the specified mark to avoid erroneous results.

7.  Twice weekly FBEs, (platelet count) and renal function are required. If there is an abrupt decrease in platelet count, (eg 50%) consult the Clinical Haematology department.

8. The duration of UFH therapy is dependent upon the primary problem. Please consult the Clinical Haematology department for guidelines. 

Precautions

1. Avoid IM injections and arterial stabs during anticoagulant therapy. When such procedures are clinically necessary, ensure adequate external pressure is applied post-procedure.
2. Lumbar punctures should not be performed while patients are on UFH therapy.
3. Avoid aspirin and other anti-platelet medications during UFH therapy.
4. UFH should be withheld prior to procedures. The timing of UFH cessation around procedures will vary depending upon the procedure to be performed and the patient's individual risk of bleeding and thrombosis. Clinical Haematology consultation is recommended in determining the timing of UFH cessation around procedures. 

Adverse Events

The major adverse event potentially related to UFH infusion is bleeding. The reported frequency of UFH-related major bleeding varies significantly, from major bleeding rates ranging from 0 to 24% of patients exposed to UFH. If a patient on UFH develops bleeding, cease UFH infusion and seek urgent Clinical Haematology consult. Heparin induced thrombocytopenia (HIT) is a potentially life-threatening UFH-related adverse event. In adults, the reported incidence ranges from 3-5%. In children, the incidence is likely much lower. Thrombocytopenia occurring in the setting of UFH therapy is likely to be secondary to patient's comorbidity. Screening for the possibility of HIT requires Clinical Haematology consultation. 

UFH Antidote

If anticoagulation with UFH needs to be discontinued for clinical reasons, termination of the UFH 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 of cardiac surgery and ICU, Clinical Haematology 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 sufhate neutralises UFH 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 UFH received in the previous 2 hours as follows: 

Table 4. Protamine dose for UFH reversal 

The maximum dose of protamine sulfate, regardless of the amount of UFH received is 50 mg except for reversal of UFH 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. 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.  

Systemic lytic therapy

This is a guideline for the use of systemic lytic therapy. There is no robust data to support the use of local lytic therapy in infants and children except for line blockages. Administration of systemic lytic therapy within the RCH requires involvement of the Clinical Haematology department. 

Indications

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

Contraindications

• Active bleeding
• Significant potential for serious local bleeding
• General surgery within the previous 10 days
• Neurosurgery within the previous 3 weeks
• AV malformations
• Recent significant trauma. 

Preparation for infusion

• Obtain patient weight, FBE, INR/PT, APTT and fibrinogen. Platelet count must be >100. Fibrinogen must be ³ 1.0. Administer FFP infusion 20ml/kg if clinically indicated. Consider administering Vitamin K if the patient could be deficient.
• Consider appropriate staffing requirements are in place to monitor infusion.
•  Ensure adequate venous access to:
• infuse lytic therapy, and
• obtain blood specimens during infusion. 
• Establish heparin infusion of 10 units/kg/hour to be administered continuously throughout lytic infusion (see Standard Heparin Infusion Clinical Practice Guideline). If possible heparin should be administered for 6 hours prior to lysis as this may reduce the likelihood of thrombus progression. Concomitant low molecular weight heparin therapy has been reported, however the limited reversibility of this agent makes it a less-preferred option compared to standard heparin. 
• tPA is the preferred lytic agent for use in children due to limited evidence regarding reduced immunogenicity, improved in vitro clot lysis, and fibrin specificity compared to urokinase and streptokinase. In some limited instances, streptokinase may be selected in preference to tPA.

DO NOT use Streptokinase if the patient has previously been exposed to streptokinase. Premedicate with paracetamol and/or promethazine due to potential for allergic reactions.

6.  Administer lytic therapy as per following guidelines:

*occasionally "front-loaded" tPA therapy is indicated. The Clinical Haematology department will discuss this option with clinical teams as indicated.

• Throughout infusion monitor:  -  pulse & BP hourly
• Inspect 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 tPA and Heparin infusions and seek urgent Clinical 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 20 units/kg/hour (no bolus). Arrange Clinical Haematology review to determine response or need for further lysis 

Treatment of bleeding secondary to thrombolytic therapy

Based upon case series reports and cohort studies, 30-50% of patients receiving systemic lytic therapy will experience a bleeding event, with approximately 11-40% of patients requiring red blood cell transfusion. An increased likelihood of bleeding is associated with a prolonged lytic therapy infusion. Minor bleeding usually presents as oozing from a wound or puncture site. Major bleeding is defined as bleeding into a body cavity (intracranial, retroperitoneal, thoracic) or external bleeding requiring transfusion.

If bleeding occurs, cease tPA and heparin infusions and seek an urgent Clinical Haematology review. Treatment with local pressure is usually sufficient management of bleeding from wound or puncture sites. Cryoprecipitate, antifibrinolytics and blood products may be indicated for the management of major bleeding. 

Precautions

• No IM injections during lytic therapy
• Minimize patient handling during infusion
• Avoid concurrent use of warfarin and antiplatelet agents
• Delay any invasive procedures such as urinary catheterization, re-siting venous/arterial access, or perform such procedures pre-lytic infusion
• One author has suggested lytic therapy is contraindicated in infants <32 weeks gestation, despite anecdotal reports existing regarding the successful use of lytic therapy in such infants. Decision making regarding the risk: benefit of lytic therapy should be made on an individualised basis  

Local

Consultation with the Clinical Haematology Department is required. Contact can be made on ext. 52605 during office hours or page the on-call Haematologist through RCH switchboard after-hours.

RCH specific information

Consultation with the Clinical Haematology Department is required for therapeutic infusions outside of the Paediatric Intensive Care Unit and Cardiac Unit. Contact can be made by paging the Inpatient Clinical Haematology Registrar on pager 5030 during office hours or page the on-call Haematologist through RCH switchboard after hours.

References

1. Monagle P, Chan A, Goldenberg N, Ichord R, Journeycake J, Nowak-Gottl U, Vesely S. 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:e737-e801S.

2. Newall F, Ignjatovic V, Johnston L, Monagle P. Unfractionated heparin therapy in infants and children. Pediatrics. 2009b;123:e510-e8.

3. Monagle P, Barnes C, Ignjatovic V, Furmedge J, Newall F, Chan A, DeRosa L, Hamilton S, Ragg P, Robinson S, Auldist A, Crock C, Rowlands S. Developmental haemostasis: Impact for clinical haemostasis laboratories. Thrombosis and Haemostasis. 2006;95:362-72.

4. Monagle P, Newall F. Anticoagulation in Children. Thrombosis Research. 2012;130:124-46.

5. Newall F, Ignjatovic V, Johnston L, Summerhayes R, Lane G, Cranswick N, Monagle P. Age is a determinant factor for measures of concentration and effect in children requiring unfractionated heparin. Thrombosis and Haemostasis. 2010a;103:1085-90.

6. Newall F, Ignjatovic V, Johnston L, Summerhayes R, Lane G, Cranswick N, Monagle P. Clinical use of unfractionated heparin therapy in children: time for change? British Journal of Haematology. 2010;150: 674-678.

7. McDonald M, Hathaway W. Anticoagulation therapy by continuous heparinization in newborn and older infants. The Journal of Pediatrics 1982;101(3):451-457.

8. Andrew M, Marzinotto V, Massicotte P, Blanchette V, Ginsberg J, Brill-Edwards P, et al. Heparin therapy in pediatric patients: a prospective cohort study. Pediatric Research 1994;35(1):78-83.

9. Chan A, Berry L, Monagle P, Andrew M. Decreased concentrations of heparinoids are required to inhibit thrombin generation in plasma from newborns and children compared to plasma from adults due to reduced thrombin potential. Thrombosis and Haemostasis 2002;87:606-13.

10. Kuhle S, Eulmesekian P, Kavanagh B, Massicotte P, Vegh P, Mitchell L. A clinically significant incidence of bleeding in critically ill children receiving therapeutic doses of unfractionated heparin: a prospective cohort study. Haematologica 2007;92(2):244-47.

11. Kuhle S, Eulmesekian P, Kavanagh B, Massicotte P, Vegh P, Lau A, et al. Lack of correlation between heparin dose and standard clinical monitoring tests in treatment with unfractionated heparin in critically ill children. Haematologica 2007;92(4):554-557.

12. Ignjatovic V, Summerhayes R, Than J, Gan A, Monagle P. Therapeutic range for unfractionated heparin therapy: age-related differences in response in children. Journal of Thrombosis and Haemostasis 2006;4(10):2280-2282.

13. Ignjatovic V, Furmedge J, Newall F, Chan A, Berry L, Fong C, et al. Age-related differences in heparin response. Thrombosis Research 2006;118(6):741-45.

14. Ignjatovic V, Summerhayes R, Gan A, Than J, Chan A, Cochrane A, et al. Monitoring unfractionated heparin (UFH) therapy: which anti factor Xa assay is appropriate? Thrombosis Research 2007;120(3):347-351.

15. Newall F, Barnes C, Ignjatovic V, Monagle P. Heparin-induced thrombocytopaenia in children. Journal of Paediatrics and Child Health 2003;39(4):289-92.

16. Infant deaths due to Heparin overdose: time for a concerted action on prevention. Monagle P, Studdert D, Newall F. Journal of Paediatrics and Child Health. 48(5):380–381. 2012.