title: Modeling the non-steady state respiratory effects of remifentanil in awake and propofol-sedated healthy volunteers.
abstract: BACKGROUND
  Few studies address the dynamic effect of opioids on respiration. Models with intact feedback control of carbon dioxide on ventilation (non-steady-state models) that correctly incorporate the complex interaction among drug concentration, end-tidal partial pressure of carbon dioxide concentration, and ventilation yield reliable descriptions and predictions of the behavior of opioids. The authors measured the effect of remifentanil on respiration and developed a model of remifentanil-induced respiratory depression.
  
  
  METHODS
  Ten male healthy volunteers received remifentanil infusions with different infusion speeds (target concentrations: 4-9 ng/ml; at infusion rates: 0.17-9 ng x ml x min) while awake and at the background of low-dose propofol. The data were analyzed with a nonlinear model consisting of two additive linear parts, one describing the depressant effect of remifentanil and the other describing the stimulatory effect of carbon dioxide on ventilation.
  
  
  RESULTS
  The model adequately described the data including the occurrence of apnea. Most important model parameters were as follows: C50 for respiratory depression 1.6 +/- 0.03 ng/ml, gain of the respiratory controller (G) 0.42 - 0.1 l x min x Torr, and remifentanil blood effect site equilibration half-life (t(1/2)ke0) 0.53 +/- 0.2 min. Propofol caused a 20-50% reduction of C50 and G but had no effect on t(1/2)ke0. Apnea occurred during propofol infusion only. A simulation study revealed an increase in apnea duration at infusion speeds of 2.5-0.5 ng x ml x min followed by a reduction. At an infusion speed of < or = 0.31 ng x ml x min, no apnea was seen.
  
  
  CONCLUSIONS
  The effect of varying remifentanil infusions with and without a background of low-dose propofol on ventilation and end-tidal partial pressure of carbon dioxide concentration was described successfully using a non-steady-state model of the ventilatory control system. The model allows meaningful simulations and predictions.
authors.affiliation: Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: Olofsen
authors.forename: Merel
authors.initials: M
authors.lastname: Boom
authors.forename: Diederik
authors.initials: D
authors.lastname: Nieuwenhuijs
authors.forename: Elise
authors.initials: E
authors.lastname: Sarton
authors.forename: Luc
authors.initials: L
authors.lastname: Teppema
authors.forename: Leon
authors.initials: L
authors.lastname: Aarts
authors.forename: Albert
authors.initials: A
authors.lastname: Dahan
mesh_terms: D000293:Adolescent; D000328:Adult; D001049:Apnea / Q000097:blood / Q000139:chemically induced; D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000097:blood*; D007260:Infusion Pumps; D008297:Male; D008954:Models, Biological; D010880:Piperidines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood*; D015742:Propofol / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood*; D000077208:Remifentanil; D015656:Respiratory Mechanics / Q000187:drug effects / Q000502:physiology*; D014851:Wakefulness / Q000187:drug effects / Q000502:physiology*; D055815:Young Adult
chemical_list: D006993:Hypnotics and Sedatives; D010880:Piperidines; D000077208:Remifentanil; D015742:Propofol