title: The dose-dependent effect of S(+)-ketamine on cardiac output in healthy volunteers and complex regional pain syndrome type 1 chronic pain patients.
abstract: BACKGROUND
  Ketamine is used as an analgesic for treatment of acute and chronic pain. While ketamine has a stimulatory effect on the cardiovascular system, little is known about the concentration-effect relationship. We examined the effect of S(+)-ketamine on cardiac output in healthy volunteers and chronic pain patients using a pharmacokinetic-pharmacodynamic modeling approach.
  
  
  METHODS
  In 10 chronic pain patients (diagnosed with complex regional pain syndrome type 1 [CRPS1] with a mean age 43.2 ± 13 years, disease duration 8.4 years, range 1.1 to 21.7 years) and 12 healthy volunteers (21.3 ± 1.6 years), 7 increasing IV doses of S(+)-ketamine were given over 5 minutes at 20-minute intervals starting with 1.5 mg with 1.5-mg increments. Cardiac output (CO) was calculated from the arterial pressure curve obtained from an arterial catheter in the radial artery. Ketamine and norketamine plasma concentrations were measured. A novel pharmacokinetic-pharmacodynamic model was constructed to quantify the direct stimulatory effect of ketamine on CO and the following adaptation/inhibition.
  
  
  RESULTS
  Significant differences in pharmacokinetic estimates were observed between study groups with 15% and 40% larger S(+)-ketamine S(+)-norketamine concentrations in healthy volunteers compared to CRPS1 patients. S(+)-ketamine had a dose-dependent stimulatory effect on CO in patients and volunteers. After infusion an inhibitory effect on CO was observed. Pharmacodynamic model parameters did not differ between CRPS1 patients and healthy volunteers. The concentration of S(+)-ketamine causing a 1 L/min increase in CO was 243 ± 54 ng/mL with an onset/offset half-life of 1.3 ± 0.21 minutes. The inhibitory component was slow (time constant of 67.2 ± 17.0 minutes).
  
  
  CONCLUSIONS
  S(+)-ketamine pharmacokinetics but not pharmacodynamics differed between study populations, related to differences in disease state (CRPS1 or not) or age. The dose-dependent effect of S(+)-ketamine on CO was well described by the biphasic dynamic model. The effect of S(+)-ketamine on CO was similar between study groups with respect to its stimulatory and inhibitory components, despite group differences in age and health.
authors.affiliation: Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: Olofsen
authors.forename: Marnix
authors.initials: M
authors.lastname: Sigtermans
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Noppers
authors.forename: Marieke
authors.initials: M
authors.lastname: Niesters
authors.forename: Rene
authors.initials: R
authors.lastname: Mooren
authors.forename: Martin
authors.initials: M
authors.lastname: Bauer
authors.forename: Leon
authors.initials: L
authors.lastname: Aarts
authors.forename: Elise
authors.initials: E
authors.lastname: Sarton
authors.forename: Albert
authors.initials: A
authors.lastname: Dahan
mesh_terms: D000328:Adult; D000700:Analgesics / Q000494:pharmacology*; D002302:Cardiac Output / Q000187:drug effects*; D059350:Chronic Pain / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007649:Ketamine / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D012019:Reflex Sympathetic Dystrophy / Q000503:physiopathology*
chemical_list: D000700:Analgesics; D007649:Ketamine