Negative drift of sedation depth in critically ill patients receiving constant minimum alveolar concentration of isoflurane, sevoflurane, or desflurane: a randomized controlled trial

Abstract

Background: Intensive care unit (ICU) physicians have extended the minimum alveolar concentration (MAC) to deliver and monitor long-term volatile sedation in critically ill patients. There is limited evidence of MAC's reliability in controlling sedation depth in this setting. We hypothesized that sedation depth, measured by the electroencephalography (EEG)-derived Narcotrend-Index (burst-suppression N_Index 0-awake N_Index 100), might drift downward over time despite constant MAC values.

Methods: This prospective single-centre randomized clinical study was conducted at a University Hospital Surgical Intensive Care Unit and included consecutive, postoperative ICU patients fulfilling the inclusion criteria. Patients were randomly assigned to receive uninterrupted inhalational sedation with isoflurane, sevoflurane, or desflurane. The end-expiratory concentration of the anaesthetics and the EEG-derived index were measured continuously in time-stamped pairs. Sedation depth was also monitored using Richmond-Agitation-Sedation-Scale (RASS). The paired t-test and linear models (bootstrapped or multilevel) have been employed to analyze MAC, N_Index and RASS across the three groups.

Results: Thirty patients were recruited (female/male: 10/20, age 64 ± 11, Simplified Acute Physiology Score II 30 ± 10). In the first 24 h, 21.208 pairs of data points (N_Index and MAC) were recorded. The median MAC of 0.58 ± 0.06 remained stable over the sedation time in all three groups. The t-test indicated in the isoflurane and sevoflurane groups a significant drop in RASS and EEG-derived N_Index in the first versus last two sedation hours. We applied a multilevel linear model on the entire longitudinal data, nested per patient, which produced the formula N_Index = 43 - 0.7·h (R2 = 0.76), showing a strong negative correlation between sedation's duration and the N_Index. Bootstrapped linear models applied for each sedation group produced: N_Index of 43-0.9, 45-0.8, and 43-0.4·h for isoflurane, sevoflurane, and desflurane, respectively. The regression coefficient for desflurane was almost half of those for isoflurane and sevoflurane, indicating a less pronounced time-effect in this group.

Conclusions: Maintaining constant MAC does not guarantee stable sedation depth. Thus, the patients necessitate frequent clinical assessments or, when unfeasible, continuous EEG monitoring. The differences across different volatile anaesthetics regarding their time-dependent negative drift requires further exploration.

Trial registration: NCT03860129.

Keywords: Critical care; Desflurane; Electroencephalography; Inhalational sedation; Isoflurane; Narcotrend; Sevoflurane.

Conflict of interest statement

Bellgardt und Herzog-Niescery received speaker's honoraria from Pall Medical, Dreieich, Germany. The other authors declare that they have no conflict of interest.

Figures

Fig. 1

CONSORT diagram for our single-centered randomized controlled trial

Fig. 2

bootstrapped histograms—each patient and group equally represented. On horizontal axis—the N_Index, the vertical axis displays the relative sampling frequency of a certain N_Index value

Fig. 3

Graphical representation of the pairwise (per patient) t-test in the first 2 h (left blue whisker) and last two sedation hours (right red whisker); each patient is representing by a grey line connecting two dots (patient’s median N_Index)

Fig. 4

The bootstrapped regression’s mean coefficients per group (slope and intercept) are displayed as blue lines. The horizontal axis is the duration of uninterrupted volatile sedation; the vertical axis is the EEG-derived sedation depth. Below the dotted red line, it is considered excessive sedation (stage E and F)