Abstract
Background
Pharmacokinetic/pharmacodynamic (PK/PD) modeling has made an enormous contribution to intravenous anesthesia. Because of their altered physiological, pharmacological and pathological aspects, titrating general anesthesia in the elderly is a challenging task.
Methods
Eighty patients were consecutively enrolled divided by decades from vicenarians (20–29 year) to nonagenarians (90–99 year) into eight groups. Using target controlled infusion (TCI) and electroencephalographic (EEG)-derived bispectral index (BIS) we set propofol plasma concentration (Cp) to gradually reach 3.5 μg mL−1 over 3.5-min. In each patient, we constructed a PK/PD model and conducted a population PK/PD (PopPK-PD) covariate analysis.
Results
Age was significant covariate for baseline BIS effect (E0), inhibitory propofol concentration at 50% BIS decline (IC50) and maximum BIS decline (Emax). First-order rate constant Ke0 of 0.47 min−1 in vicenarians (20–29 year) gradually increased with age-progression to 1.85 min−1 in nonagenarians (90–99 year). Simulation modelling showed that clinically recommended Cp of 3.5 μg mL−1 for 20–29 year BIS 50 should be reduced to 3.0 for 30–49 year, 2.5 for 50–69 year and 2.0 for 80–89 year.
Conclusion
We quantified and graded EEG-BIS age-progression among different age groups divided by decades. We demonstrated deeper BIS values with decades’ age progression. Our data has important implications for propofol dosing. The practical information for physicians in their daily clinical practice is using propofol Cp of 3.5 μg mL−1 might not yield BIS value of 50 in elderly patients. Our simulations showed that the recommended regimen of Cp 3.5 μg mL−1 for 20–29 year should be gradually decreased to 2.0 μg mL−1 for 80–89 year.
Clinical trial registry numbers
European Community Clinical Trials Database EudraCT (http://eudract.emea.eu) initial trial registration number: 2011-002847-81, and subsequently registered at www.clinicaltrials.gov; trial registration number: NCT02585284. Xijing Hospital of Fourth Military Medical University ethics committee approval number 20110707-4.
Similar content being viewed by others
References
Ergina P, Gold S, Meakins J (1993) Perioperative care of the elderly patient. World J Surg 17:192–198
Sahinovic MM, Struys MMRF, Absalom AR (2018) Clinical pharmacokinetics and pharmacodynamics of propofol. Clin Pharmacokinet 57:1539–1558
Tarr L, Oppenheimer B, Sager R (1933) The circulation time in various clinical conditions determined by the use of sodium dehydrochlorate. Am Heart J 8:766
Raoof AA, Augustijns PR, Verbeeck RK (1996) In vivo assessment of intenstinal, hepatic, and pulmonary first pass metabolism of propofol in the rat. Pharm Res 13:891–895
Dawidowicz AL, Kalitynski R, Fijalkowska A (2003) Free and bound propofol concentrations in human cerebrospinal fluid. Br J Clin Pharmacol 56:545–550
Engdahl O, Abrahams M, Björnsson A et al (1998) Cerebrospinal fluid concentrations of propofol during anaesthesia in humans. Br J Anaesth 81:957–959
Minto CF, Schnider TW (2008) Contributions of PK/PD modeling to intravenous anesthesia. Clin Pharmacol Ther 84:27–38
Eleveld DJ, Proost JH, Cortínez LI, Absalom AR, Struys MMRF (2014) A general purpose pharmacokinetic model for propofol. Anesth Analg 118:1221–1237
Eleveld DJ, Colin P, Absalom AR, Struys MMRF (2018) Pharmacokinetic-pharmacodynamic model for propofol for broad application in anaesthesia and sedation. Br J Anaesth 120:942–959
Schnider TW, Minto CF, Gambus PL et al (1998) The influence of method of administration and covariates on the pharmacokinetics of propofol in adult volunteers. Anesthesiology 88:1170–1182
Schnider TW, Minto CF, Shafer SL et al (1999) The influence of age on propofol pharmacodynamics. Anesthesiology 90:1502–1516
Sigl JC, Chamoun NG (1994) An introduction to bispectral analysis for the electroencephalogram. J Clin Monit 10:392–404
Lysakowski C, Dumont L, Pellegrini M, Clergue F, Tassonyi E (2001) Effects of fentanyl, alfentanil, remifentanil, and sufentanil on loss of consciousness and bispectral index during propofol induction of anaesthesia. Br J Anaesth 86:523–527
Bossuyt PM, Reitsma JB, Bruns DE et al (2003) The STARD statement for reporting studies of diagnostic accuracy: explanation and elaboration. Clin Chemistry 49:7–18
Folstein MF, Folstein SE, McHugh PR (1975) ‘Mini-mental state’. A practical method for grading the cognitive state of patients for the clinician. J Psychiatric Research 12:189–198
Laalou FZ, Egard M, Guillot M, Noll E, Taglang G, Pain L (2010) Influence of preoperative cognitive status on propofol requirement to maintain hypnosis in the elderly. Br J Anaesth 105:342–346
Renna M, Handy J, Shah A (2003) Low baseline Bispectral Index of the electroencephalogram in patients with dementia. Anesth Analg 96:1380–1385
Dahaba AA, Xue JX, Xu GX, Liu QH, Metzler H (2011) Bilateral Bispectral Index (BIS)-Vista as a measure of physiologic sleep in sleep-deprived anaesthesiologists. Minerva Anestesiol 77:388–393
Dahaba AA, Bornemann H, Hopfgartner, et al. Effect of sugammadex or neostigmine neuromuscular block reversal on bispectral index monitoring of propofol/remifentanil anaesthesia. Br J Anaesth. 2011; 108: 602–606.
Mathews DM, Kumaran KR, Neuman GG (2003) Bispectral index-derived facial electromyography-guided fentanyl titration in the opiate-exposed patient. Anesth Analg 96:1062–1064
Smith C, McEwan AI, Jhaveri R et al (1994) The interaction of fentanyl on the Cp50 of propofol for loss of consciousness and skin incision. Anesthesiology 81:820–828
Dixon WJ, Massey FJ (1983) Introduction to statistical analysis, 4th edn. McGraw-Hill, New York, pp 426–441
Absalom AR, Mani V, De Smet T, Struys MM (2009) Pharmacokinetic models for propofol–defining and illuminating the devil in the detail. Br J Anaesth 103:26–37
Dahaba AA, Zhong T, Lu HS et al (2011) Geographic differences in target-controlled infusion estimated concentration of propofol: bispectral index response curves. Can J Anaesth 58:364–370
Buhrer M, Maitre PO, Hung OR, Ebling WR, Shafer SL, Stanski DR (1992) Thiopental pharmacodynamics: defining the pseudo-steady-state serum concentration-EEG effect relationship. Anesthesiology 77:226–236
Chernik DA, Gillings D, Laine H et al (1990) Validity and reliability of the Observer’s Assessment of Alertness/Sedation Scale: study with intravenous midazolam. J Clin Psychopharmacol 10:244–251
Dahaba AA, Lischnig U, Kronthaler R et al (2006) Bispectral-index-guided versus clinically guided remifentanil/propofol analgesia/sedation for interventional radiological procedures: an observer-blinded randomized study. Anesth Analg 103:378–384
Dahaba AA, Prax N, Gaube W, Gries M, Rehak PH, Metzler H (2006) Haemodynamic and catecholamine stress responses to Laryngeal Tube-Suction Airway and the Proseal Laryngeal Mask Airway. Anaesthesia 61:330–334
Mandema JW, Verotta D, Sheiner LB (1992) Building population pharmacokinetic–pharmacodynamic models. I. Models for covariate effects. J Pharmacokinet Biopharm 20:511–528
Zhang L, Beal SL, Sheiner LB (2003) Simultaneous vs sequential analysis for population PK/PD data I: best-case performance. J Pharmacokinet Pharmacodyn 30:387–404
Lindbom L, Ribbing J, Jonsson EN (2004) Perl-speaks-NONMEM (PsN): a Perl module for NONMEM related programming. Comput Methods Progr Biomed 75:85–94
Katoh T, Bito H, Sato S (2000) Influence of age on hypnotic requirement, bispectral index, and 95% spectral edge frequency associated with sedation induced by sevoflurane. Anesthesiology 92:55–61
Vernon JM, Lang E, Sebel PS, Manberg P (1995) Prediction of movement using bispectral electroencephalographic analysis during propofol/alfentanil or isoflurane/alfentanil anesthesia. Anesth Analg 80:780–785
Sebel PS, Lang E, Rampil IJ et al (1997) A multicenter study of bispectral electroencephalogram analysis for monitoring anesthetic effect. Anesth Analg 84:891–899
Ouattara A, Boccara G, Lemaire S et al (2003) Target-controlled infusion of propofol and remifentanil in cardiac anaesthesia: influence of age on predicted effect-site concentrations. Br J Anaesth 90:617–622
Kazama T, Ikeda K, Morita K et al (1999) Comparison of the effect-site ke0s of propofol for blood pressure and EEG bispectral index in elderly and younger patients. Anesthesiology 90:1517–1527
Sheiner LB, Rosenberg B, Melmon KL (1972) Modelling of individual pharmacokinetics for computer-aided drug dosage. Comput Biomed Res 5:411–459
Sheiner LB, Sheiner LB, Stanski DR, Vozeh S, Miller RD, Ham J (1979) Simultaneous modeling of pharmacokinetics and pharmacodynamics: application to d-tubocurarine. Clin Pharmacol Ther 25:358–371
Holford NH, Sheiner LB (1981) Understanding the dose-effect relationship: clinical application of pharmacokinetic-pharmacodynamic models. Clin Pharmacokinet 6:429–453
Cortínez LI (2014) What is the ke0 and what does it tell me about propofol? Anaesthesia 69:399–402
Wang Y, Kikuchi T, Sakai M, Wu JL, Sato K, Okumura F (2000) Age-related modifications of effects of ketamine and propofol on rat hippocampal acetylcholine release studied by in vivo brain microdialysis. Acta Anaesthesiol Scand 44:112–117
Larsson JE, Wahlstrom G (1998) The influence of age and administration rate on the brain sensitivity to propofol in rats. Acta Anaesthesiol Scand 42:987–994
Schultz A, Grouven U, Zander I, Beger FA, Siedenberg M, Schultz B (2004) Age-related effects in the EEG during propofol anaesthesia. Acta Anaesthesiol Scand 48:27–34
Roubicek J (1977) The electroencephalogram in the middle-aged and the elderly. J Am Geriatr Soc 25:145–152
Lysakowski C, Elia N, Czarnetzki C et al (2009) Bispectral and spectral entropy indices at propofol-induced loss of consciousness in young and elderly patients. Br J Anaesth 103:387–393
Guignard B, Menigaux C, Dupont X, Fletcher D, Chauvin M (2000) The effect of remifentanil on the bispectral index change and hemodynamic responses after orotracheal intubation. Anesth Analg 90:161–167
Pan Y, Li D, Chen S, Pan H (2004) Activation of μ-opioid receptors excites a population of locus coeruleus-spinal neurons through presynaptic disinhibition. Brain Res 997:67–78
Bouillon T, Bruhn J, Radu-Radulescu L, Bertaccini E, Park S, Shafer S (2002) Non-steady state analysis of the pharmacokinetic interaction between propofol and remifentanil. Anesthesiology 97:1350–1362
Lampotang S, Lizdas DE, Derendorf H, Gravenstein N, Lok B, Quarles JP (2016) Race-specific pharmacodynamic model of propofol-induced loss of consciousness. J Clin Pharmacol 56:1141–1150
Acknowledgements
All authors would like to thank Dr. Fengyan Xu, M.S. and Mr. Shuiyu Zhao, Shanghai Qiangshi Information Technology Co. Ltd., Shanghai, People’s Republic of China our two brilliant Kineticists for their great efforts in the data preparation, data streaming and their NONMEM pharmacokinetic statistical analysis. Thanks to them we have all these simulations and plotted figures. We would like to thank the great efforts of Renate Oberreither for her tremendous help and efforts with the samples assay.
Funding
The study was financed from National Natural Science Foundation of China (Beijing, People’s Republic of China), Grant No.: 81471373, and the National Natural Science Foundation of China (Beijing, People’s Republic of China), Grant No.: 81071052, both grants awarded to Professor Dr. Zhaoyang Xiao, Department of Anesthesiology, Xijing First Affiliated Hospital of Fourth Military Medical University, Xi’an, Shaanxi, and Department of Anesthesiology, Second Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China.
Author information
Authors and Affiliations
Contributions
AAD: Primary investigator, conducted the study, participated in data collection, data analysis and manuscript writing. ZX: participated in perioperative anesthesia management, conducting the study, data collection, data analysis and manuscript writing. XZ: participated in perioperative anesthesia management, conducting the study and data collection, data analysis and manuscript writing. SZ: did the blood sample acquisition, handling, processing and propofol concentration assay. HD: participated in patients’ recruitment, fully informing/consenting patients, perioperative anaesthesia management and conducting the study as well as the team leader of the study project trouble shooting and problem solving. LX: participated in patients’ recruitment, fully informing/consenting patients, perioperative anesthesia management and conducting the study as well as trouble shooting and problem solving. PR: was the original methodologist for the study and he did the first statistical analysis before he passed away. KW: is the pharmacometrician who designed the population pharmacokinetic-pharmacodynamic analysis. GR: is Medical Chemist. He worked out the mathematics of the logistic model. He did fitting of the data to models.
Corresponding author
Ethics declarations
Conflict of interest
All authors attest to the validity and legitimacy of the data and its interpretation, and agree to its submission. All authors have significantly contributed to the manuscript and no person or group of persons who actively contributed were excluded from the study. All authors confirm that they have read and approved the paper, have met the criteria for authorship as established by the International Committee of Medical Journals Editors, believe that the paper represents honest work, and are able to verify the validity of the results reported. All authors state that we have absolutely no conflicts of interest (including financial, consultant, institutional and other relationships that might lead to bias or a conflict of interest). None of the authors received honoraria from a company or were on the speaker’s bureau for any Organization, and there were no sources of financial support, corporate involvement or patent holdings other than the above mentioned grants from the Scientific Research Fund of Ministry of Health - Major Plan of Science and from above mentioned departmental sources. There was no support whatsoever from a pharmaceutical company or a manufacturer in editing of the protocol, financial support, drug supply, data analysis or writing of the paper.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Dahaba, A.A., Xiao, Z., Zhu, X. et al. Age progression from vicenarians (20–29 year) to nonagenarians (90–99 year) among a population pharmacokinetic/pharmacodynamic (PopPk-PD) covariate analysis of propofol-bispectral index (BIS) electroencephalography. J Pharmacokinet Pharmacodyn 47, 145–161 (2020). https://doi.org/10.1007/s10928-020-09678-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10928-020-09678-0