Antithrombotic Therapy in Children: Heparin Therapy in Pediatric Patients
Doses: The doses of heparin required in pediatric patients to achieve adult therapeutic APTT values have been assessed using a weight-based nomogram (one level IV study).12 A bolus dose of 50 U/kg was insufficient, resulting in subtherapeutic APTT values in 60% of children. Bolus doses of 75 to 100 U/kg result in therapeutic APTT values in 90% of children (M. Andrew, MD; unpublished data; 1995). Maintenance heparin doses are age dependent, with infants having the highest requirements (28 U/kg/h) and children over 1 year of age having lower requirements (20 U/kg/h) (Table 1). The doses of heparin required for older children are similar to the weight-adjusted requirements in adults (18 U/kg/h). The duration of heparin therapy for the treatment of deep vein thrombosis (DVT) is a minimum of 5 days, and 7 to 10 days for extensive DVT or pulmonary embolism (PE). Oral anticoagulant therapy can be initiated on day 1 of heparin therapy, except for extensive DVT or PE, when oral anticoagulant therapy should be delayed.
Pharmacokinetics: There are at least two plausible explanations for the increased heparin requirement in young children. Canadianfamilypharmacy First, heparin is cleared more quickly in the young compared to the adult in animal models and humans. Second, the delay in diagnosis of thrombotic complications in children may result in more extensive disease at the time of presentation, accelerating heparin clearance.
Monitoring: Appropriate dosage adjustment of IV heparin therapy can be problematic. Nomograms are convenient to use and have been successful in achieving therapeutic APTT levels in a timely manner in adults. A nomogram initially used in adults was adapted, tested and modified for children (Table 1). Heparin dosing nomograms can be adapted into preprinted order sheets, which facilitate rapid anticoagulation.
Adverse Effects: There are at least three clinically important adverse effects of heparin. First, bleeding, a major complication of heparin in adults, is discussed in detail elsewhere in this supplement. One level IV study in children suggests that major bleeding from heparin therapy is not frequent in the treatment of DVT or PE in children.12 However, many children were treated with suboptimal amounts of heparin in this study,12 and there are case reports of major bleeding due to heparin in children. The risk of bleeding may increase when therapeutic doses of heparin are used more uniformly, particularly in children with serious underlying disorders. A second adverse effect is osteoporosis. There is no information on the occurrence of osteoporosis in children receiving heparin therapy. However, given the convincing relationship between heparin and osteoporosis in adults, long-term use of heparin in children should be avoided when other alternative anticoagulants are available. The third adverse effect is the association of thrombocytopenia with heparin therapy in pediatric patients.24-26 In the absence of an alternative etiology for heparin-associated thrombocytopenia, pediatric patients should be evaluated for heparin-induced thrombocytopenia (HIT) and treated with alternative therapy. Protocols for the use of danap-aroid in adults have been adapted for children but there is limited experience with their use27 (Table 2).
Table 1—Protocol for Systemic Heparin Administration and Adjustment for Pediatric Patients
|I. Loading dose: heparin 75 U/kg IV over 10 minII. Initial maintenance dose: 28 U/kg/h for infants younger than 1 yrIII. Initial maintenance dose: 20 U/kg/h for children older than 1 yrIV. Adjust heparin to maintain APTT 60 to 85 s (assuming this reflects an anti-factor Xa level of 0.30 to 0.70):|
|APTT, s||Bolus, U/kg||Hold, min||% Rate Change||Repeat APTT|
|<50||50||0||+ 10||4 h|
|50-59||0||0||+ 10||4 h|
|V. Obtain blood for APTT 4 h after administration of the heparin loading dose and 4 h after every change in the infusion rateVI. When APTT values are therapeutic, a daily CBC and APTT|
Table 2—Protocol for the Use of Orgaran (Danaparoid Sodium) in Pediatric Patients
|Orgaran consists mainly of heparin sulfate, a small quantity of dermatan sulfate and a minor amount of chondroitin sulfate, and does not contain any heparin fragments. Orgaran has a much higher anti-Xa/anti-IIa ratio compared to heparin or LMWH. Orgaran has a decreased cross reactivity rate (<10%) with heparin-induced antibody as compared to LMWH (>90%).|
|Loading Dose:||30 U/kg body weight|
|Initial Maintenance Dose:||1.2-2.0 U/kg/h|
|Monitoring:||Anti-factor Xa activity can be monitored immediately following the bolus dose, every 4 h until steady state is reached, and then daily to maintain a therapeutic range of 0.4-0.8 U/mL|
|Orgaran is predominantly removed from the circulation through the kidney.Consequently, Orgaran is contraindicated in patients with severe impaired renal function.Subcutaneous Orgaran is frequently used in adults, although there is no published pediatric dose information.|