Pharmacokinetics and pharmacodynamics of dopamine and norepinephrine in critically ill head-injured patients

Objective: To explore the pharmacokinetics and pharmacodynamics of dopamine and norepinephrine. Design: Prospective, controlled, trial. Setting: Neurosciences critical care unit. Patients: Eight patients with a head injury, requiring dopamine or norepinephrine infusions to support cerebral perfusion pressure (CPP). Intervention: Patients received in randomised order, either dopamine or norepinephrine to achieve and maintain a CPP of 70 mmHg, and then, following a 30-min period of stable haemodynamics, a CPP of 90 mmHg. Data were then acquired using the second agent. Haemodynamic measurements were made during each period and a blood sample was obtained at the end of each study period for analysis of plasma catecholamine concentrations Measurements and results: Plasma levels of norepinephrine and dopamine were significantly related to infusion rates but did not have a simple linear relationship to haemodynamic parameters. However, there was a significant quadratic relationship between the infusion rate of dopamine and cardiac index (r(2)=0.431), and systemic vascular resistance index (r(2)=0.605), with a breakpoint (at which cardiac index reduced and SVRI increased) at a dopamine plasma level of similar to50 nM/I (corresponding to an infusion rate of similar to15 mug-kg(-1).min(-1)). Conclusions: Norepinephrine and dopamine have predictable pharmacokinetics; however, those of dopamine do not fit a simple first-order kinetic model. The pharmacodynamic effects of dopamine and norepinephrine show much inter-individual variability and unpredictability. Plasma levels of dopamine appear to relate to variations in adrenergic receptor effects with break points that reflect expectations from infusion-rate related pharmacodynamics.