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

TL;DR

This study finds that isoflurane sedation reduces liver enzyme activity in ICU patients, similar to the effect of sepsis.

Contribution

The novel finding is that isoflurane, like sepsis, decreases CYP1A2 activity, impacting liver function tests in critically ill patients.

Findings

LiMAx values decreased significantly during isoflurane sedation in both septic and non-septic ICU patients.

Sepsis and isoflurane independently reduce hepatic CYP1A2 activity, with a possible mechanism involving HIF-1α upregulation.

Lactate levels increased during isoflurane use, suggesting increased anaerobic metabolism without clinical consequences.

Abstract

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.

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.

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.

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.

The online version contains supplementary material available at 10.1186/s40635-024-00617-8.

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