Isoflurane, like sepsis, decreases CYP1A2 liver enzyme activity in intensive care patients: a clinical study and network model

Thomas Köhler; Elke Schwier; Janina Praxenthaler; Carmen Kirchner; Günther Winde; Björn Koos; Dietrich Henzler

doi:10.1186/s40635-024-00617-8

Isoflurane, like sepsis, decreases CYP1A2 liver enzyme activity in intensive care patients: a clinical study and network model

Intensive Care Med Exp. 2024 Apr 8;12(1):33. doi: 10.1186/s40635-024-00617-8.

Authors

Thomas Köhler^{1

2}, Elke Schwier³, Janina Praxenthaler^{3

4}, Carmen Kirchner⁵, Günther Winde⁵, Björn Koos⁶, Dietrich Henzler³

Affiliations

¹ Department of Anesthesiology, Surgical Intensive Care, Emergency and Pain Medicine, Ruhr University Bochum, Klinikum Herford, Herford, Germany. Thomas.koehler@ruhr-uni-bochum.de.
² Department of Anesthesiology and Intensive Care Medicine, AMEOS-Klinikum Halberstadt, Academic Teaching Hospital, Gleimstraße 5, 38820, Halberstadt, Germany. Thomas.koehler@ruhr-uni-bochum.de.
³ Department of Anesthesiology, Surgical Intensive Care, Emergency and Pain Medicine, Ruhr University Bochum, Klinikum Herford, Herford, Germany.
⁴ Department of Anesthesiology, Intensive Care and Pain Medicine, Southeast Bavaria Hospitals, Klinikum Traunstein, Traunstein, Germany.
⁵ Department of General and Visceral Surgery, Thoracic Surgery and Proctology, Ruhr University Bochum, Klinikum Herford, Herford, Germany.
⁶ Department of Anesthesiology, Intensive Care and Pain Medicine, Ruhr University Bochum, Knappschaftskrankenhaus Bochum GmbH, Bochum, Germany.

Abstract

Purpose: Liver function of intensive care patients is routinely monitored by static blood pathology. For specific indications, liver specific cytochrome activity may be measured by the commercially available maximum liver function capacity (LiMAx) test via quantification of the cytochrome P450 1A2 (CYP1A2) dependent C-methacetin metabolism. Sedation with the volatile anesthetic isoflurane was suspected to abrogate the correlation of LiMAx test with global liver function. We hypothesized that isoflurane has a CYP1A2-activity and LiMAx test result decreasing effect.

Methods: In this monocentric, observational clinical study previously liver healthy intensive care patients, scheduled to be changed from propofol to isoflurane sedation, were enrolled. LiMAx testing was done before, during and after termination of isoflurane sedation.

Results: The mean LiMAx value decreased during isoflurane sedation. Septic patients (n = 11) exhibited lower LiMAx values compared to non-septic patients (n = 11) at all time points. LiMAx values decreased with isoflurane from 140 ± 82 to 30 ± 34 µg kg^-1 h^-1 in the septic group and from 253 ± 92 to 147 ± 131 µg kg^-1 h^-1 in the non-septic group while laboratory markers did not imply significant hepatic impairment. Lactate increased during isoflurane inhalation without clinical consequence.

Conclusion: Sepsis and isoflurane have independently demonstrated an effect on reducing the hepatic CYP1A2-activity. A network model was constructed that could explain the mechanism through the influence of isoflurane on hypoxia inducible factor (HIF-1α) by upregulation of the hypoxia-inducible pathway and the downregulation of CYP1A2-activity via the ligand-inducible pathway. Thus, the increased anaerobic metabolism may result in lactate accumulation. The influence of isoflurane sedation on the validated correlation of global liver function with CYP1A2-activity measured by LiMAx testing needs to be investigated in more detail.

Keywords: Cytochrome P450 1A2; Hypoxia inducible factor; Isoflurane; LiMAx; Maximum liver function capacity test; Sepsis.