title: An exploration of remifentanil-propofol combinations that lead to a loss of response to esophageal instrumentation, a loss of responsiveness, and/or onset of intolerable ventilatory depression.
abstract: BACKGROUND
  Remifentanil and propofol are increasingly used for short-duration procedures in spontaneously breathing patients. In this setting, it is preferable to block the response to moderate stimuli while avoiding loss of responsiveness (LOR) and intolerable ventilatory depression (IVD). In this study, we explored selected effects of combinations of remifentanil-propofol effect-site concentrations (Ces) that lead to a loss of response to esophageal instrumentation (EI), LOR, and/or onset of IVD. A secondary aim was to use these observations to create response surface models for each effect measure. We hypothesized that (1) in a large percentage of volunteers, selected remifentanil and propofol Ces would allow EI but avoid LOR and IVD, and (2) the drug interaction for these effects would be synergistic.
  
  
  METHODS
  Twenty-four volunteers received escalating target-controlled remifentanil and propofol infusions over ranges of 0 to 6.4 ng · mL(-1) and 0 to 4.3 μg · mL(-1), respectively. At each set of target concentrations, responses to insertion of a blunt end bougie into the midesophagus (40 cm), level of responsiveness, and respiratory rate were recorded. From these data, response surface models of loss of response to EI and IVD were built and characterized as synergistic, additive, or antagonistic. A previously published model of LOR was used.
  
  
  RESULTS
  Of the possible 384 assessments, volunteers were unresponsive to EI at 105 predicted remifentanil-propofol Ces; in 30 of these, volunteers had no IVD; in 30, volunteers had no LOR; and in 9, volunteers had no IVD or LOR. Many other assessments over the same concentration ranges, however, did have LOR and/or IVD. The combinations that allowed EI and avoided IVD and/or LOR primarily clustered around remifentanil-propofol Ces ranging from 0.8 to 1.6 ng · mL(-1) and 1.5 to 2.7 μg · mL(-1), respectively, and to a lesser extent approximately 3.0 to 4.0 ng · mL(-1) and 0.0 to 1.1 μg · mL(-1), respectively. Models of loss of response to EI and IVD both demonstrated a synergistic interaction between remifentanil and propofol.
  
  
  CONCLUSIONS
  Selected remifentanil-propofol concentration pairs, especially higher propofol-lower remifentanil concentration pairs, can block the response to EI while avoiding IVD in spontaneously breathing volunteers. It is, however, difficult to block the response to EI and avoid both LOR and IVD. It may be necessary to accept some discomfort and blunt rather than block the response to EI to consistently avoid LOR and IVD.
authors.affiliation: Department of Anesthesiology, University of Utah, 30 North 1900 East, Salt Lake City, UT 84132-2304, USA.
authors.forename: Cris D
authors.initials: CD
authors.lastname: LaPierre
authors.forename: Ken B
authors.initials: KB
authors.lastname: Johnson
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Randall
authors.forename: Julia L
authors.initials: JL
authors.lastname: White
authors.forename: Talmage D
authors.initials: TD
authors.lastname: Egan
mesh_terms: D000328:Adult; D019162:Anesthetics, Combined / Q000008:administration & dosage / Q000009:adverse effects*; D018686:Anesthetics, Intravenous / Q000008:administration & dosage / Q000009:adverse effects*; D001364:Awareness / Q000187:drug effects; D016009:Chi-Square Distribution; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004947:Esophagus / Q000187:drug effects* / Q000503:physiopathology; D005260:Female; D006801:Humans; D007260:Infusion Pumps; D007262:Infusions, Intravenous; D008297:Male; D015233:Models, Statistical; D010880:Piperidines / Q000008:administration & dosage / Q000009:adverse effects*; D015742:Propofol / Q000008:administration & dosage / Q000009:adverse effects*; D000077208:Remifentanil; D012131:Respiratory Insufficiency / Q000139:chemically induced* / Q000503:physiopathology; D056152:Respiratory Rate / Q000187:drug effects; D012677:Sensation / Q000187:drug effects*; D013525:Surgical Instruments; D013997:Time Factors; D014589:Utah; D055815:Young Adult
chemical_list: D019162:Anesthetics, Combined; D018686:Anesthetics, Intravenous; D010880:Piperidines; D000077208:Remifentanil; D015742:Propofol