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In-silico analysis of closed-loop vasopressor control of phenylephrine versus norepinephrine

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Abstract

We have previously demonstrated in in-silico, pre-clinical animal models, and finally human clinical studies the ability of a novel closed-loop vasopressor titration system to manage norepinephrine infusion rates to keep mean arterial blood pressure in a very tight range, reduce hypotension time and severity, and reduce overtreatment. We hypothesized that the same controller could, with modification for pharmacologic differences, suitably titrate a lower-potency longer duration of action agent like phenylephrine. Using the same physiologic simulation model as was used previously for in-silico testing of our controller for norepinephrine, we first updated the model to include a new vasopressor agent modeled after phenylephrine. A series of simulation tests patterned after our previous norepinephrine study was then conducted, this time using phenylephrine for management, in order to both test the system with the new agent and allow for comparisons between the two. Hundreds of simulation trials were conducted across a range of patient and environmental variances. The controller performance was characterized based on time in target, time above and below target, coefficient of variation, and using Varvel’s criteria. The controller kept the simulated patients’ MAP in target for 94% of management time in the simple scenarios and more than 85% of time in the most challenging scenarios. Varvel criteria were all under 1% error for expected pharmacologic responses and were consistent with those established for norepinephrine in our previous studies. The controller was able to acceptably titrate phenylephrine in this simulated patient model consistent with performance previously seen for norepinephrine after adjusting for the anticipated differences between the two agents.

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Data availability

By request to corresponding author.

Code availability

Simulator available by request to corresponding author.

References

  1. Rinehart J, Joosten A, Ma M, Calderon MD, Cannesson M. Closed-loop vasopressor control: in-silico study of robustness against pharmacodynamic variability. J Clin Monit Comput. 2019;33(5):795–802.

    Article  Google Scholar 

  2. Joosten A, Delaporte A, Alexander B, Su F, Creteur J, Vincent JL, Cannesson M, Rinehart J. Automated titration of vasopressor infusion using a closed-loop controller. Anesthesiology. 2019;130(3):394–403.

    Article  CAS  Google Scholar 

  3. Rinehart J, Ma M, Calderon MD, Cannesson M. Feasibility of automated titration of vasopressor infusions using a novel closed-loop controller. J Clin Monit Comput. 2018;32(1):5–11.

    Article  Google Scholar 

  4. Rinehart J, Cannesson M, Weeraman S, Barvais L, Obbergh LV, Joosten A. Closed-loop control of vasopressor administration in patients undergoing cardiac revascularization surgery. J Cardiothorac Vasc Anesth. 2020;34(11):3081–5.

    Article  Google Scholar 

  5. Joosten A, Coeckelenbergh S, Alexander B, Cannesson M, Rinehart J. Feasibility of computer-assisted vasopressor infusion using continuous non-invasive blood pressure monitoring in high-risk patients undergoing renal transplant surgery. Anaesth Crit Care Pain Med. 2020;39(5):623–4.

    Article  Google Scholar 

  6. Joosten A, Alexander B, Duranteau J, Taccone FS, Creteur J, Vincent JL, Cannesson M, Rinehart J. Feasibility of closed-loop titration of norepinephrine infusion in patients undergoing moderate- and high-risk surgery. Br J Anaesth. 2019;123(4):430–8.

    Article  CAS  Google Scholar 

  7. Joosten A, Rinehart J, Van der Linden P, Alexander B, Penna C, De Montblanc J, Cannesson M, Vincent JL, Vicaut E, Duranteau J. Computer-assisted individualized hemodynamic management reduces intraoperative hypotension in intermediate- and high-risk surgery: a randomized controlled trial. Anesthesiology. 2021;135:258–72.

    Article  CAS  Google Scholar 

  8. Joosten A, Chirnoaga D, Van der Linden P, Barvais L, Alexander B, Duranteau J, Vincent JL, Cannesson M, Rinehart J. Automated closed-loop versus manually controlled norepinephrine infusion in patients undergoing intermediate- to high-risk abdominal surgery: a randomised controlled trial. Br J Anaesth. 2021;126(1):210–8.

    Article  CAS  Google Scholar 

  9. Michard F, Liu N, Kurz A. The future of intraoperative blood pressure management. J Clin Monit Comput. 2018;32(1):1–4.

    Article  Google Scholar 

  10. Hulting J, Thorstrand C. Hemodynamic effects of norepinephrine in severe hypnotic drug poisoning with arterial hypotension. Acta Med Scand. 1972;192(5):447–53.

    CAS  PubMed  Google Scholar 

  11. Kroppenstedt SN, Thomale UW, Griebenow M, Sakowitz OW, Schaser KD, Mayr PS, Unterberg AW, Stover JF. Effects of early and late intravenous norepinephrine infusion on cerebral perfusion, microcirculation, brain-tissue oxygenation, and edema formation in brain-injured rats. Crit Care Med. 2003;31(8):2211–21.

    Article  CAS  Google Scholar 

  12. Cavus E, Meybohm P, Dorges V, Stadlbauer KH, Wenzel V, Weiss H, Scholz J, Bein B. Regional and local brain oxygenation during hemorrhagic shock: a prospective experimental study on the effects of small-volume resuscitation with norepinephrine. J Trauma. 2008;64(3):641–8.

    CAS  PubMed  Google Scholar 

  13. Xu T, Zheng J, An XH, Xu ZF, Wang F. Norepinephrine intravenous prophylactic bolus versus rescue bolus to prevent and treat maternal hypotension after combined spinal and epidural anesthesia during cesarean delivery: a sequential dose-finding study. Ann Transl Med. 2019;7(18):451.

    Article  CAS  Google Scholar 

  14. Rokyta R Jr, Tesarova J, Pechman V, Gajdos P, Krouzecky A. The effects of short-term norepinephrine up-titration on hemodynamics in cardiogenic shock. Physiol Res. 2010;59(3):373–8.

    Article  CAS  Google Scholar 

  15. Redl-Wenzl EM, Armbruster C, Edelmann G, Fischl E, Kolacny M, Wechsler-Fordos A, Sporn P. The effects of norepinephrine on hemodynamics and renal function in severe septic shock states. Intensive Care Med. 1993;19(3):151–4.

    Article  CAS  Google Scholar 

  16. Christensen LK, Armstead VE, Bilyeu DP, Johnson KE, Friesen RH. Hemodynamic responses and plasma phenylephrine concentrations associated with intranasal phenylephrine in children. Paediatr Anaesth. 2017;27(7):768–73.

    Article  Google Scholar 

  17. Brassard P, Pelletier C, Martin M, Gagne N, Poirier P, Ainslie PN, Caouette M, Bussieres JS. Influence of norepinephrine and phenylephrine on frontal lobe oxygenation during cardiopulmonary bypass in patients with diabetes. J Cardiothorac Vasc Anesth. 2014;28(3):608–17.

    Article  CAS  Google Scholar 

  18. Wang X, Mao M, Zhang SS, Wang ZH, Xu SQ, Shen XF. Bolus norepinephrine and phenylephrine for maternal hypotension during elective cesarean section with spinal anesthesia: a randomized, double-blinded study. Chin Med J (Engl). 2020;133(5):509–16.

    Article  Google Scholar 

  19. Wang X, Mao M, Liu S, Xu S, Yang J. A comparative study of bolus norepinephrine, phenylephrine, and ephedrine for the treatment of maternal hypotension in parturient with preeclampsia during caesarean delivery under spinal anesthesia. Med Sci Monit. 2019;25:1093–101.

    Article  CAS  Google Scholar 

  20. Kwak YL, Lee CS, Park YH, Hong YW. The effect of phenylephrine and norepinephrine in patients with chronic pulmonary hypertension*. Anaesthesia. 2002;57(1):9–14.

    Article  CAS  Google Scholar 

  21. Chou J, Rinehart JB. Computer simulated modeling of healthy and diseased right ventricular and pulmonary circulation. J Clin Monit Comput. 2018;32(6):1015–24.

    Article  Google Scholar 

  22. Rinehart J, Alexander B, Le Manach Y, Hofer C, Tavernier B, Kain ZN, Cannesson M. Evaluation of a novel closed-loop fluid-administration system based on dynamic predictors of fluid responsiveness: an in silico simulation study. Crit Care. 2011;15(6):R278.

    Article  Google Scholar 

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Acknowledgements

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Funding

No funding was provided except for departmental support of the authors.

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Authors and Affiliations

  1. Department of Anesthesiology and Perioperative Care, University of California Irvine, 101 The City Drive South, Orange, CA, 92660, USA

    Michael Ma, Angela Ho & Joseph Rinehart

  2. Department of Anesthesiology, Intensive Care and Perioperative Medicine, Bicêtre Hospital, 78, Rue du Général Leclerc, Le Kremlin-Bicêtre, 94270, France

    Alexandre Joosten

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  1. Michael Ma
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  2. Angela Ho
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  3. Alexandre Joosten
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  4. Joseph Rinehart
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Contributions

MM—Performed simulations, analysis, and drafting of the manuscript. AH—Sourced drug references, performed simulations, drafting of manuscript. AJ, JR—Study design, analysis, drafting of manuscript.

Corresponding author

Correspondence to Joseph Rinehart.

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Conflict of interest

Michael Ma, Angela Ho—None. Alexandre Joosten, Joseph Rinehart—Consultant for Edwards Lifesciences, equity interest in Perceptive Medical Inc.

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Ma, M., Ho, A., Joosten, A. et al. In-silico analysis of closed-loop vasopressor control of phenylephrine versus norepinephrine. J Clin Monit Comput 36, 1305–1313 (2022). https://doi.org/10.1007/s10877-021-00761-6

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  • DOI: https://doi.org/10.1007/s10877-021-00761-6

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