Catecholamine pharmacokinetics and pharmacodynamics in critical illness

Objective

Despite their widespread use, there are limited data on the pharmacokinetics and pharmacodynamics of dopamine (DA) and norepinephrine (NE) in critically ill patients. We have addressed these issues in a randomised cross-over study in a group of head-injured patients.

Methods

Eight patients with a head injury, requiring DA or NE infusions to support cerebral perfusion pressure (CPP), were recruited following informed assent from patients' next of kin. Patients received in randomised order either DA or NE 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; plasma was stored for later analysis of catecholamine levels by high performance liquid chromatography. Data were analysed with paired t tests and regression analysis using Statview 4 (SAS), with P < 0.05 treated as significant.

Results

Plasma levels of NE and DA were significantly related to infusion rates (Fig. 1), but neither predicted haemodynamic parameters. However, there was a significant quadratic relationship between the infusion rate of DA and CI (r² = 0.431), and SVRI (r² = 0.605), with a breakpoint (at which the CI reduced and the SVRI increased) at a DA plasma level of ~50 nM/l (corresponding to an infusion rate of ~15 μg/kg per min).

Conclusions

NE and DA have predictable pharmacokinetics; however, those of DA do not fit a simple first-order kinetic model. The pharmacodynamic effects of DA and NE show much inter-individual variability and unpredictability. DA plasma levels appear to relate to variations in adrenergic receptor effects with break points that reflect expectations from infusion rate related pharmacodynamics.

Figure 1