Wolstencroft P, Arnold P, Anderson BJ.
Pediatric Anesthesia. 2021;31:637-43.
DOI: 10.1111/pan.14125
PMID: 33423355
Take Home Points
- Bivalirudin clearance rates decrease with age
- Higher bivalirudin infusion rates in children will achieve target blood plasma concentrations without the need for dose titration
- After loading dose of 2.5 mg/kg, bivalirudin infusion at a rate of 4.5 mg/kg/hour in a 10 kg child, 4 mg/kg/hour in a 20 kg child, and 3.5 mg/kg/hour in a 30-40 kg child will produce an ACT < 400 seconds
- Children ≥ 50 kg should follow adult dosing protocols
Commentary by Kelly A Machovec, MD, MPH, Associate Professor of Anesthesiology, Duke University Hospital.
Bivalirudin is a direct thrombin inhibitor used as an alternative to heparin anticoagulation in cases of heparin induced thrombocytopenia with thrombosis, severe antithrombin deficiency, or anaphylaxis to protamine. Bivalirudin is metabolized by intracellular proteolysis, with 20% excreted unchanged by the kidneys. Wolstencroft, Arnold and Anderson present a study using allometry to determine appropriate bivalirudin infusion rates for pediatric patients requiring bivalirudin for cardiopulmonary bypass (CPB) anticoagulation1.
Previous studies in healthy adults demonstrate that a target bivalirudin plasma concentration of 10-15 mg/L is sufficient to maintain effective anticoagulation, as guided by activated clotting time (ACT)2. Bivalirudin anticoagulation reaches a ceiling ACT value of about 450 seconds in the adult population. However, pharmacokinetic and pharmacodynamic studies for bivalirudin in adults undergoing procedures with CPB have not been widely conducted; dosing in this population is extrapolated from studies of both healthy adults and those having percutaneous cardiac procedures2,3. For CPB, generally accepted dosing in adults is a loading dose of 1 mg/kg followed by an infusion of 2.5 mg/kg/hour, to achieve a target ACT of 350-500 seconds.
Bivalirudin pharmacokinetics have been studied in children with congenital heart disease having cardiac catheterization procedures, who received a bolus loading dose of 0.75 mg/kg, then infusion of 1.75 mg/kg/hour4. The authors of this PK study demonstrated that bivalirudin clearance decreases with age, with neonates and infants (less than 2 years) having the highest clearance. Interestingly, the authors postulate that the immature renal system in neonates and young infants, which should decrease bivalirudin clearance, is likely balanced by enhanced proteolytic degradation in the blood. As in adults, bivalirudin has a ceiling effect on the ACT, with maximum ACT of approximately 400 seconds4.
Neither adult dosing regimens nor pediatric percutaneous cardiac dosing regimens are appropriate for dosing bivalirudin in children undergoing cardiac procedures with CPB. Wolstencroft, Arnold and Anderson address this knowledge gap by using allometry to determine pediatric dosing of bivalirudin5. Allometric theory states that the clearance of bivalirudin should be the same in children as in adults, as long as the dose is scaled for the child’s weight using the following equation:
Infusion rateChild = Infusion rateAdult x (WeightChild/70)0.75
The authors propose that, given the derangements to hemostasis and coagulation induced by CPB, the following infusion rates should be used after bivalirudin loading dose:
- 10 kg – 4.5 mg/kg/hour
- 20 kg – 4 mg/kg/hour
- 30-40 kg – 3.5 mg/kg/hour
- 50 kg – adult dosing
These rates will produce an ACT less than 400 seconds. However, the authors emphasize the importance of avoiding changes to the infusion rate to chase a given ACT. After increasing the infusion rate, it takes about 3-5.5 half-lives to reach a new steady-state, so changes based on the ACT will eventually accumulate and risk excessive anticoagulation and bleeding complications.
What this means for our practice
Bivalirudin dosing in children having cardiac surgery with CPB cannot simply be adopted from adult protocols. Adult dosing does not consider developmental hemostasis and its impact on coagulation and fibrinolysis. Further, adult regimens do not account for unique aspects of pediatric cardiac procedures, including hypothermia, prolonged aortic cross-clamp times, and the use of ultrafiltration. Each of these aspects of pediatric CPB affects bivalirudin clearance.
Using allometric theory, bivalirudin infusion rates can be extrapolated from adult data and applied to children of a given body weight. After a loading dose of 2.5 mg/kg, the infusion should be started at the rate indicated by the child’s weight and then not adjusted, despite ACT values that are out of the intended range for CPB. Doing so may result in unintentional over- or under-dosing with potentially deleterious consequences. Unfortunately, no point-of-care tests for bivalirudin efficacy are yet available for clinical use.
The dosing regimen for neonates and infants is still uncertain despite the allometric methods applied in this study. The combination of immature renal function and immature coagulation/fibrinolytic systems will affect bivalirudin clearance, but research to date does not demonstrate the magnitude of these effects. This is a topic in need of further investigation.
References
1. Wolstencroft P, Arnold P, Anderson BJ. Dose estimation for bivalirudin during pediatric cardiopulmonary bypass. Paediatr Anaesth. 2021;31(6):637-643.
2. Zhang DM, Wang K, Zhao X, et al. Population pharmacokinetics and pharmacodynamics of bivalirudin in young healthy Chinese volunteers. Acta Pharmacol Sin. 2012;33(11):1387-1394.
3. Robson R, White H, Aylward P, Frampton C. Bivalirudin pharmacokinetics and pharmacodynamics: effect of renal function, dose, and gender. Clin Pharmacol Ther. 2002;71(6):433-439.
4. Forbes TJ, Hijazi ZM, Young G, et al. Pediatric catheterization laboratory anticoagulation with bivalirudin. Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions. 2011;77(5):671-679.
5. Anderson BJ, Meakin GH. Scaling for size: some implications for paediatric anaesthesia dosing. Paediatr Anaesth. 2002;12(3):205-219.
