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Optimizing intraoperative administration of propofol, remifentanil, and fentanyl through pharmacokinetic and pharmacodynamic simulations to increase the postoperative duration of analgesia

  • Carl TamsEmail author
  • Noah Syroid
  • Terrie Vasilopoulos
  • Ken Johnson
Original Research
  • 47 Downloads

Abstract

Titrating an intraoperative anesthetic to achieve the postoperative goals of rapid emergence and prolonged analgesia can be difficult because of inter-patient variability and the need to provide intraoperative sedation and analgesia. Modeling pharmacokinetics and pharmacodynamics of anesthetic administrations estimates drug concentrations and predicted responses to stimuli during anesthesia. With utility of these PK/PD models we created an algorithm to optimize the intraoperative dosing regimen. We hypothesized the optimization algorithm would find a dosing regimen that would increase the postoperative duration of analgesia, not increase the time to emergence, and meet the intraoperative requirements of sedation and analgesia. To evaluate these hypotheses we performed a simulation study on previously collected anesthesia data. We developed an algorithm to recommend different intraoperative dosing regimens for improved post-operative results. To test the post-operative results of the algorithm we tested it on previously collected anesthesia data. An anesthetic dataset of 21 patients was obtained from a previous study from an anesthetic database at the University of Utah. Using the anesthetic records from these surgeries we modeled 21 patients using the same patient demographics and anesthetic requirements as the dataset. The anesthetic was simulated for each of the 21 patients with three different dosing regimens. The three dosing regimens are: from the anesthesiologist as recorded in the dataset (control group), from the algorithm in the clinical scenario one (test group), and from the algorithm in the clinical scenario two (test group). We created two clinical scenarios for the optimization algorithm to perform; one with normal general anesthesia constraints and goals, and a second condition where a delayed time to emergence is allowed to further maximize the duration of analgesia. The algorithm was evaluated by comparing the post-operative results of the control group to each of the test groups. Comparing results between the clinical scenario 1 dosing to the actual dosing showed a median increase in the duration of analgesia by 6 min and the time to emergence by 0.3 min. This was achieved by decreasing the intraoperative remifentanil infusion rate, increased the fentanyl dosing regimen, and not changing the propofol infusion rate. Comparing results between the clinical scenario 2 dosing to the actual dosing showed a median increase in the duration of analgesia by 26 min and emergence by 1.5 min. To dosing regimen from clinical scenario 2 greatly increased the fentanyl dosing regimen and greatly decreased the remifentanil infusion rate with no change to the propofol infusion rate. The results from this preliminary analysis of the optimization algorithm appear to imply that it can operate as intended. However a clinical study is warranted to determine to what extent the optimization algorithm determined optimal dosing regimens can maximize the postoperative duration of analgesia without delaying the time to emergence in a clinical setting.

Keywords

Anesthesia Pharmacokinetic Pharmacodynamic Total intravenous anesthesia Optimization 

Notes

Supplementary material

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Supplementary material 1 (DOCX 10 KB)
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Supplementary material 3 (DOCX 59 KB)
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Supplementary material 4 (DOCX 2 MB)

References

  1. 1.
    Egan T. Remifentanil pharmacokinetics and pharmacodynamics. A preliminary appraisal. Clin Pharmacokinet. 1995;29(2):80–94.CrossRefGoogle Scholar
  2. 2.
    Egan T. The pharmacokinetics of the new short-acting opioid remifentanil (GI87074B) in healthy adult male volunteers. Anesthesiology. 1993;79:881–92.CrossRefGoogle Scholar
  3. 3.
    Schnider T, Minto C, Gambus P, Andresen C, Goodale D, Shafer S, Youngs E. The influence of method of administration and covariates on the pharmacokinetics of propofol in adult volunteers. Anesthesiology. 1998;88(5):1170–82.CrossRefGoogle Scholar
  4. 4.
    Schnider T, Minto C, Shafer S, Gambus P, Andresen C, Goodale D, Youngs E. The influence of age on propofol pharmacodynamics. Anesthesiology. 1999;90(6):1502–16.CrossRefGoogle Scholar
  5. 5.
    Shafer S, Varvel J, Aziz N, Scott J. Pharmacokinetics of fentanyl administered by computer-controlled infusion pump. Anesthesiology. 1990;73(6):1091–102.CrossRefGoogle Scholar
  6. 6.
    Minto C, Schnider T, Egan T, Youngs E, Lemmens H, Gambus P, Billard V, Hoke J, Moore K, Hermann D, Muir K, Mandema J, Shafer S. Influence of age and gender on the pharmacokinetics and pharmacodynamic of remifentanil. I. Model development. Anesthesiology. 1997;86(1):10–23.CrossRefGoogle Scholar
  7. 7.
    Minto C, Schnider T, Shafer S. Pharmacokinetics and pharmacodynamics of remifentanil. II Model application. Anesthesiology. 1997;86(1):24–33.CrossRefGoogle Scholar
  8. 8.
    Bouillon T. Pharmacodynamic interaction between propofol and remifentanil regarding hypnosis, tolerance of laryngoscopy, Bispectral index, and electroencephalographic approximate entropy. Anesthesiology. 2004;100:1353–72.CrossRefGoogle Scholar
  9. 9.
    Kern S. Opioid hypnotic synergy. Anesthesiology. 2004;100:1373–81.CrossRefGoogle Scholar
  10. 10.
    Johnson K, Syroid N, Gupta D, Manyam S, Egan T, Huntington J, White J, Tyler D, Westenskow D. An evaluation of remifentanil propofol response surfaces for loss of responsiveness, loss of response to surrogates of painful stimuli and laryngoscopy in patients undergoing elective surgery. Anesth Analg. 2008;106:471–9.CrossRefGoogle Scholar
  11. 11.
    Lapierre C, Johnson K, Randall B, White J, Egan T. 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. Anesth Analg. 2011;113(3):490–9.Google Scholar
  12. 12.
    Vuyk J. Propofol anesthesia and rational opioid selection. Anesthesiology. 1997;87(6):1549–62.CrossRefGoogle Scholar
  13. 13.
    Syroid N, Agutter J, Drews F, Westenskow D, Albert R, Bermudez J, Strayer D, Prenzel H, Loeb R, Weinger M. Development and evaluation of a graphical anesthesia drug display. Anesthesiology. 2002;96:565–74.CrossRefGoogle Scholar
  14. 14.
    Cirillo V, Marinosci G, Robertis E, Iacono C, Romano G, Desantis O, Piazza O, Servillo G, Tufano R. Navigator and Smartpilot are helpful in guiding anesthesia and reducing anesthetic drug dosing. Minerv Anesth. 2015;81:1163–9.Google Scholar
  15. 15.
    Liu N, Chazot T, Hamada S, Landals A, Bolchut N, Dussaussoy C, Trillat B, Beydon L, Samain E, Sessler D, Fischler M. Closed-loop coadministration of propofol and remifentanil guided by bispectral index: a randomized multicenter study. Anesth Analg. 2011;112:546–57.CrossRefGoogle Scholar
  16. 16.
    Struys M, Sahinovic M, Lichtenbelt B, Vereecke H, Absalom A. Optimizing intravenous drug administration by applying pharmacokinetic/pharmacodynamic concepts. Br J Anaesth. 2011;107(1):38–47.CrossRefGoogle Scholar
  17. 17.
    Van Den Berg J, Vereecke H, Proost J, Eleveld D, Wietasch J, Absalom A, Struys M. Pharmacokinetic and pharmacodynamic interactions in anesthesia. A review of current knowledge and how it can be used to optimize anesthetic drug administration. Br J Anesth. 2017;118(1):44–57.CrossRefGoogle Scholar
  18. 18.
    Tams C, Johnson K. Prediction variability of combined pharmacokinetic pharmacodynamic models: a simulation study of propofol in combination with remifentanil and fentanyl. J Anesth Clin Res. 2014;5:393.  https://doi.org/10.4172/2155-6148.1000393.CrossRefGoogle Scholar
  19. 19.
    Shafer S. All models are wrong. Anesthesiology. 2012;116(2):240–1.CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Department of AnesthesiologyUniversity of UtahSalt Lake CityUSA
  2. 2.MedVisSalt Lake CityUSA
  3. 3.Department of AnesthesiologyUniversity of FloridaGainesvilleUSA

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