Sevoflurane dose and postoperative delirium: a prospective cohort analysis

Abstract

Background: Recent trials are conflicting as to whether titration of anaesthetic dose using electroencephalography monitoring reduces postoperative delirium. Titration to anaesthetic dose itself might yield clearer conclusions. We analysed our observational cohort to clarify both dose ranges for trials of anaesthetic dose and biological plausibility of anaesthetic dose influencing delirium.

Methods: We analysed the use of sevoflurane in an ongoing prospective cohort of non-intracranial surgery. Of 167 participants, 118 received sevoflurane and were aged >65 yr. We tested associations between age-adjusted median sevoflurane (AMS) minimum alveolar concentration fraction or area under the sevoflurane time×dose curve (AUC-S) and delirium severity (Delirium Rating Scale-98). Delirium incidence was measured with 3-minute Diagnostic Confusion Assessment Method (3D-CAM) or CAM-ICU. Associations with previously identified delirium biomarkers (interleukin-8, neurofilament light, total tau, or S100B) were tested.

Results: Delirium severity did not correlate with AMS (Spearman's ρ=-0.014, P=0.89) or AUC-S (ρ=0.093, P=0.35), nor did delirium incidence (AMS Wilcoxon P=0.86, AUC-S P=0.78). Further sensitivity analyses including propofol dose also demonstrated no relationship. Linear regression confirmed no association for AMS in unadjusted (log (IRR)=-0.06 P=0.645) or adjusted models (log (IRR)=-0.0454, P=0.735). No association was observed for AUC-S in unadjusted (log (IRR)=0.00, P=0.054) or adjusted models (log (IRR)=0.00, P=0.832). No association of anaesthetic dose with delirium biomarkers was identified (P>0.05).

Conclusion: Sevoflurane dose was not associated with delirium severity or incidence. Other biological mechanisms of delirium, such as inflammation and neuronal injury, appear more plausible than dose of sevoflurane.

Clinical trial registration: NCT03124303, NCT01980511.

Keywords: anaesthesia; biomarker; cognitive dysfunction; delirium; dose dependency; postoperative; sevoflurane; surgery.

Fig 1

Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) diagram.

Fig 2

Correlations between sevoflurane dose, delirium severity, and delirium incidence in 111 participants. Spearman's correlation and Wilcoxon tests were used: (a) and (c) excludes seven outliers for DRS∼AMS, and (b) and (d) excludes eight outliers for DRS∼raw AUC-S. AMS, age-adjusted median sevoflurane minimum alveolar concentration fraction; AUC, area under the curve for sevoflurane (time×dose); DRS, Delirium Rating Scale Revised-98; ρ, rho, Spearman's correlation.

Fig 3

Correlations between sevoflurane dose, delirium severity, and delirium incidence on postoperative day 1. Spearman's correlation and Wilcoxon tests were used. Seven outliers were excluded for DRS∼AMS. POD1 peak delirium severity includes complete cases only (n=101). AMS, age-adjusted median sevoflurane minimum alveolar concentration fraction; DRS, Delirium Rating Scale Revised-98; POD, postoperative day; ρ, rho, Spearman's correlation.

Fig 4

Causal diagram. Figure 4 presents a causal diagram depicting possible mechanisms for postoperative delirium. Hypothetical pathways whereby anaesthetic dose, as controlled by the anaesthetist, could play a causal role in postoperative delirium incidence are depicted by dashed lines. The hypothesis that risk of delirium is reduced by titration of anaesthetic dose to achieve a particular brain state (as reflected by processed EEG) is depicted as a feedback loop including the anaesthetist. Solid lines show effects with strong evidence, while dashed lines suggest unproved links. We have not drawn all the confounders and their interactions in this causal diagram for simplicity, but there are multiple confounders that should be considered for different interactions.