Dosages
Side effects in children
Warnings & precautions in children
Contra-indications in children

Interactions
PK
Renal impairment
References

Heparin

Generic name
Heparin
Brand name
ATC Code
B01AB01

Pharmacokinetics in children

Age has a significant impact on plasma concentration and the effects of unfractionated heparin. In infants and younger children, lower heparin levels and a lower anti-Xa effect were observed when the same IU/kg dose was administered than in older children (Newall et al. 2010).

Most factors and inhibitors of the development of anticoagulation system in both premature (GA ≥30 weeks) and term neonates reach adult values by 6 months of age, however contact factors (XI, XII, PK, HMWK) values still remained significant lower than the adult values. One of the exceptions is protein C as this values remain low at 6 months of age. There were however some factors that were elevated at birth and the postnatal period compared to adult values: FVIII, vWF, and the thrombin inhibitor x2M. The APTT was prolonged during first 6 months of life. The PT was comparable to those of adults, although there was variability and did shorten in newborns {Andrew 1988; Andrew 1987].

In comparison, a mean higher clearance, an increased volume of distribution and a shorter half-life were observed in 25 premature babies (McDonald et al., 1981):

 

Age groups 25-28 weeks GA1 (n=10) 29-32 weeks GA1 (n=7) 33-36 weeks GA1 (n=8) 6 months -15,5 years2

 Adults (n=8)1
T½ min  41,6 35,5 35,5 45,6  63,3 (30-180)*
Clearance (mL/kg/min)  1,49 1,43 1,37 0,6  0,43
Vd (mL/kg) 81 73,3 57,8 37,3  36,6

Table 1: The mean PK of heparin in neonates, children and adults. *Elimination half-life increase with increasing the dose.
1: McDonald et al 1981
2: Newall et al. 2009

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dose recommendation of formulary compared to licensed use (on-label versus off-label)

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Available formulations

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Dosages

Treatment thromboembolism
  • Intravenous
    • Premature and Term neonate
      [27] [28] [29] [30] [31]
      • Initial dose: (only if necessary) 50 - 75 IU/kg/dose, once only as a 10 minute infusion or as a bolus.
      • Maintenance dose: 28 IU/kg/hour, continuous infusion.

      • Monitoring primarily according to Anti-Xa (target 0.35-0.70 U / ml) or according to aPTT (target range which correlating to an Anti-Xa of 0.35-0.70 U / ml).

    • 1 month up to 12 months
      [3] [27] [28] [29] [30]
      • Initial dose: 50 - 75 IU/kg/dose, once only as a 10 minute infusion or as a bolus.
      • Maintenance dose: 28 IU/kg/hour, continuous infusion.

      • Monitoring primarily according to Anti-Xa (target 0.35-0.70 U / ml) or according to aPTT (target range which correlating to an Anti-Xa of 0.35-0.70 U / ml).

    • 1 year up to 18 years
      • Initial dose: 50 - 75 IU/kg/dose, once only as a 10 minute infusion or as a bolus. Max: 5.000 IU/dose.
      • Maintenance dose: 18 - 20 IU/kg/hour, continuous infusion.

      • Monitoring primarily according to Anti-Xa (target 0.35-0.70 U / ml) or according to aPTT (target range which correlates to an Anti-Xa of 0.35-0.70 U / ml).
Heparin lock
  • Route of administration not applicable
    • 0 years up to 18 years

      • There is very little evidence in children for this indication. Consult the topical protocol.
Thromboprophylaxis in patients at risk of thrombosis (combination of risk factors such as central venous catheter, surgery, immobilization, intensive care etc.)
  • Intravenous
    • Preterm neonates Gestational age < 37 weeks
      [3] [7] [15] [17] [18] [19] [22] [23] [24] [31] [32] [33]
      • 5 - 10 IU/kg/hour, continuous infusion.

      • There are hardly any data for the prophylactic use of heparin. The prophylactic dose must be selected depending on the indication and after consultation of a pediatric blood coagulation expert.

    • Term neonate
      [3] [15] [17] [18] [19] [22] [23] [24]
      • 5 - 10 IU/kg/hour, continuous infusion.

      • There are hardly any data for the prophylactic use of heparin. The prophylactic dose must be selected depending on the indication and after consultation of a pediatric blood coagulation expert.

         

    • 1 month up to 18 years
      [3] [15] [17] [18] [19] [22] [23] [24]
      • 5 - 10 IU/kg/hour, continuous infusion.

      • There are hardly any data for the prophylactic use of heparin. The prophylactic dose must be selected depending on the indication and after consultation of a pediatric blood coagulation expert.
Thromboprophylaxis in patients undergoing cardiac catheterization
  • Intravenous
    • Premature neonates Gestational age < 37 weeks
      [3] [12] [13] [14] [16] [20] [21] [31]
      • Initial dose: 50 - 100 IU/kg/dose, once only. Additional doses: If the procedure lasts longer, another dose of 50 IU/kg/dose can be given after 2 hours; alternatively: 28 IU/kg/h continuously during the procedure..

      • There is no evidence is found for the use of heparin for this indication in preterm neonates.

    • Term neonate
      [3] [12] [13] [14] [16] [20] [21]
      • Initial dose: 50 - 100 IU/kg/dose, once only. Additional doses: If the procedure lasts longer, another dose of 50 IU/kg/dose can be given after 2 hours; alternatively: 28 IU/kg/h continuously during the procedure..
    • 1 month up to 1 year
      [3] [12] [13] [14] [16] [20] [21]
      • Initial dose: 50 - 100 IU/kg/dose, once only. Additional doses: If the procedure lasts longer, another dose of 50 IU/kg/dose can be given after 2 hours; alternatively: 28 IU/kg/h continuously during the procedure..
    • 1 year up to 18 years
      [3] [12] [13] [14] [16] [20] [21]
      • Initial dose: 50 - 100 IU/kg/dose, once only. Additional doses: If the procedure lasts longer, another dose of 50 IU/kg/dose can be given after 2 hours; alternatively: 20 IU/kg/h continuously during the procedure..
ECMO heparinization
  • Intravenous
    • Premature neonates, term neonates and children 1 month up to 18 years

      • For extracorporal circulation (haemodialysis, ECMO etc.) it is recommended to follow institutional protocols.

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Renal impaiment in children > 3 months

GFR ≥10 ml/min/1.73m2: Dose adjustment not required.

GFR <10 ml/min/1.73m2: A general recommendation on dose adjustment cannot be provided.

Patients on dialysis

Heparin can be used as an anticoagulant during dialysis.

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The complete list of all undesirable drug reactions can be found in the national Summary of Product Characteristics (SmPC) – click here

Side effects in children

Bleeding, HITT syndrome (heparin-induced thrombocytopenia and thrombosis)

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The complete list of all contra-indications can be found in the national Summary of Product Characteristics (SmPC) – click here

Contra-indications in children

Formulations that contain benzyl alcohol must not be administered to premature infants or neonates.

The complete list of all warnings and precautions can be found in the national Summary of Product Characteristics (SmPC) – click here

Warnings & precautions in children

Do not use or reduce the dose if there is a significant risk of bleeding. Monitor thrombocytes.
Note: administer protamine for overdoses.
 

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Interactions

The complete list of all interactions can be found in the national Summary of Product Characteristics (SmPC) – click here

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Heparin group
B01AB04
B01AB05
B01AB06
Platelet aggregation inhibitors excl. heparin
B01AC06

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References

  1. Massicotte P, et al, An open-label randomized controlled trial of low molecular weight heparin for the prevention of central venous line-related thrombotic complications in children: the PROTEKT trial, Thromb Res, 2003, 109(2-3), 101-8
  2. Gal P, et al, Neonatal thrombosis: treatment with heparin and thrombolytics, DICP, 1991, 25(7-8):, 853-6
  3. Monagle P, et al , 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(2 Suppl):, e737S-801S
  4. Newall F, et al, Unfractionated heparin therapy in infants and children, Pediatrics, 2009, 123(3), e510-8
  5. Newall F, et al, Age is a determinant factor for measures of concentration and effect in children requiring unfractionated heparin, Thromb Haemost, 2010, May;103(5), 1085-90
  6. Uslu S, et al, The effect of low-dose heparin on maintaining peripherally inserted percutaneous central venous catheters in neonates, J Perinatol, 2010, Dec;30(12), 794-9
  7. Shah PS, et al, Continuous heparin infusion to prevent thrombosis and catheter occlusion in neonates with peripherally placed percutaneous central venous catheters, Cochrane Database Syst Rev, 2008, (2), CD002772
  8. Kamala F, et al, Randomized controlled trial of heparin for prevention of blockage of peripherally inserted central catheters in neonates, Acta Paediatr, 2002, 91(12), 1350-6
  9. Mok E, et al, A randomized controlled trial for maintaining peripheral intravenous lock in children, Int J Nurs Pract, 2007, Feb;13(1), 33-45
  10. McDonald, MM, et al., Heparin clearance in the newborn, Pediatr Res, 1981, 15, 1015-1018
  11. Newall, F, et al. , Unfractionated heparin has an age-dependent pharmacokinetic profile in children, J Thromb Haemost, 2009, 7(s2), 774
  12. Bulbul, Z. R., et al., Arterial complications following cardiac catheterization in children less than 10 kg., Asian Cardiovasc Thorac Ann, 2002, 10 (2), 129-32
  13. Avila, M. L., et al, Different unfractionated heparin doses for preventing arterial thrombosis in children undergoing cardiac catheterization, Cochrane Database Syst, 2020, Rev 2 (2), Cd010196
  14. Chen, D., et al., Thrombin formation and effect of unfractionated heparin during pediatric cardiac catheterization., Catheter Cardiovasc Interv, 2013, 81(7), 1174-9
  15. Yu, J. S., , Prospective Side by Side Comparison of Outcomes and Complications With a Simple Versus Intensive Anticoagulation Monitoring Strategy in Pediatric Extracorporeal Life Support Patients., Pediatr Crit Care Med, 2017, 18 (11), 1055-1062
  16. Hanslik, A., et al. 2011. , Incidence of thrombotic and bleeding complications during cardiac catheterization in children: comparison of high-dose vs. low-dose heparin protocols., J Thromb Haemost, 2011, 9 (12), 2353-60
  17. Hentschel, R., et al, Coagulation-associated complications of indwelling arterial and central venous catheters during heparin prophylaxis--a prospective study, Eur J Pediatr, 1999, 158 Suppl 3, S126-9
  18. Kessel, A. D., et al, The Impact and Statistical Analysis of a Multifaceted Anticoagulation Strategy in Children Supported on ECMO: Performance and Pitfalls., J Intensive Care Med, 2017, 32 (1), 59-67
  19. Kim, J. K., et al., Assessment of prophylactic heparin infusion as a safe preventative measure for thrombotic complications in pediatric kidney transplant recipients weighing <20 kg., Pediatr Transplant, 2019, 23 (6), e13512
  20. Roschitz, B., et al . , Signs of thrombin generation in pediatric cardiac catheterization with unfractionated heparin bolus or subcutaneous low molecular weight heparin for antithrombotic cover, Thromb Res , 2003, 111 (6), 335-41
  21. Saxena, A., et al. , Predictors of arterial thrombosis after diagnostic cardiac catheterization in infants and children randomized to two heparin dosages., Cathet Cardiovasc Diagn, 1997, 41 (4), 400-3
  22. Schroeder, A. R.,et al. , A continuous heparin infusion does not prevent catheter-related thrombosis in infants after cardiac surgery, Pediatr Crit Care Med, 2010, 11 (4), 489-95
  23. Sharathkumar, A., et al., Primary thromboprophylaxis with heparins for arteriovenous fistula failure in pediatric patients., J Vasc Access, 2007, 8 (4):, 235-44
  24. Vorisek, C. N., et al., High-dose heparin is associated with higher bleeding and thrombosis rates in pediatric patients following cardiac surgery., J Thorac Cardiovasc Surg, 2019, 158 (4), 1199-1206
  25. Andrew M, et al., Development of the human coagulation system in the healthy premature infant., Blood, 1988, 72(5), 1651-7
  26. Andrew M, et al , Development of the human coagulation system in the full-term infant, Blood, 1987, 70(1), 165-72
  27. Andrew M, et al., Heparin therapy in pediatric patients: a prospective cohort study, Pediatr Res, 1994, 35(1), 78-83
  28. McDonald MM, et al, Anticoagulant therapy by continuous heparinization in newborn and older infants., J Pediatr., 1982, 101(3), 451-7
  29. Mousa A, et al., Management of Extremity Venous Thrombosis in Neonates and Infants: An Experience From a Resource Challenged Setting., Clin Appl Thromb Hemost, 2019, 25, 1076029618814353
  30. Schechter T, et al. , Unfractionated heparin dosing in young infants: clinical outcomes in a cohort monitored with anti-factor Xa levels., J Thromb Haemost, 2012, 10(3), 368-74
  31. Werkgroep Neonatale Farmacologie NVK sectie Neonatologie., Expert opinie, 12 December 2023
  32. Alpan G, et al., Heparinization of alimentation solutions administered through peripheral veins in premature infants: a controlled study., Pediatrics, 1984, 74(3), 375-8
  33. Barrington KJ., Umbilical artery catheters in the newborn: effects of heparin. , Cochrane Database Syst Rev. , 2000, 1999(2), Cd000507

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