Pharmacokinetics and pharmacodynamics of dopamine and norepinephrine in critically ill head-injured patients.
OBJECTIVE
To explore the pharmacokinetics and pharmacodynamics of dopamine and norepinephrine.


METHODS
Prospective, controlled, trial.


METHODS
Neurosciences critical care unit.


METHODS
Eight patients with a head injury, requiring dopamine or norepinephrine infusions to support cerebral perfusion pressure (CPP).


METHODS
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


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 (r2=0.431), and systemic vascular resistance index (r2=0.605), with a breakpoint (at which cardiac index reduced and SVRI increased) at a dopamine plasma level of approximately 50 nM/l (corresponding to an infusion rate of approximately 15 microg.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.
Johnston
Andrew J
AJ
University of Cambridge Department of Anaesthetics, Addenbrooke's Hospital, Box 93, Cambridge, CB2 2QQ, United Kingdom. ajj29@cam.ac.uk
Steiner
Luzius A
LA
O'Connell
Mark
M
Chatfield
Dot A
DA
Gupta
Arun K
AK
Menon
David K
DK
D000328:Adult; D002316:Cardiotonic Agents / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D002395:Catecholamines / Q000097:blood; D006259:Craniocerebral Trauma / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D016638:Critical Illness / Q000628:therapy; D018592:Cross-Over Studies; D004298:Dopamine / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D007427:Intracranial Pressure / Q000187:drug effects; D016014:Linear Models; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009638:Norepinephrine / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D011446:Prospective Studies; D014655:Vascular Resistance / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology
D002316:Cardiotonic Agents; D002395:Catecholamines; D014662:Vasoconstrictor Agents; D004298:Dopamine; D009638:Norepinephrine