Adjunctive Sedation with Dexmedetomidine for the Prevention of Severe Inflammation and Septic Encephalopathy: A Pilot Randomized Controlled Study

Abstract

Objectives: Septic encephalopathy (SE) occurs in up to 50% of critically ill patients with sepsis and is associated with a high mortality and morbidity. The pathophysiology of SE is complex and involves increased levels of inflammatory mediators. Commonly used sedative drugs, such as propofol and midazolam, may worsen neuronal inflammation. Dexmedetomidine (DEX) has been shown to decrease the production of inflammatory mediators in experimental models of sepsis. The aim of this study was to investigate the effect of DEX on biomarkers associated with SE in critically ill patients with sepsis.

Design: Pilot, open-label, randomized controlled clinical trial.

Setting: Single-center University Hospital, Switzerland.

Patients: Adult patients with sepsis admitted to the ICU, who required intubation and ongoing sedative medication between September 1, 2019, and June 30, 2022.

Interventions: DEX-based sedation compared with propofol and/or midazolam-based sedation and serum S100-β level at 48 hr after randomization.

Measurements and main results: The study included 70 participants with 34 (48.6%) randomized to the DEX group and 36 (51.4%) to the propofol/midazolam group. Median S100-β levels in the DEX group at 48 hr were 0.103 (interquartile range 0.052-0.194) ng/ml, and in the propofol/midazolam group 0.189 (0.086-0.368) ng/mL ( p = 0.064). Other biomarker showed no differences over time. In patients with a Glasgow Coma Scale less than or equal to 13, the median S100-β level in the DEX group was 0.13 ng/mL (0.06-0.18) compared to 0.91 ng/mL (0.43-0.96) in the propofol/midazolam group ( p = 0.033).

Conclusions: DEX-based sedation compared to propofol/midazolam-based sedation did not show any significant difference in S100-β or any other markers of SE in critically ill patients with sepsis requiring mechanical ventilation. The finding of lower S100-β levels in DEX-sedated patients with GCS less than 13 warrants further investigation.

Trial registration: ClinicalTrials.gov NCT04076826.

Keywords: dexmedetomidine; inflammation; sedatives; sepsis; septic encephalopathy.

Figure 1.

Consort flow chart. *A detailed list of exclusion criteria is presented in the Supplementary Appendix (http://links.lww.com/CCM/H704).

Figure 2.

Cumulative doses of sedative drugs and peak dose of norepinephrin. A, Cumulative dose of dexmedetomidine in µg/kg/hr shown as box and scatterplots with trending lines between median peak dose. B, Cumulative dose of propofol in mg/kg/hr shown as box and scatterplots with trending lines between median cumulative doses. Baseline refers to the dose received at randomization. C, Cumulative dose of midazolam in mg/kg/hr shown as box and scatterplots with trending lines between median cumulative doses. Baseline refers to the dose received at randomization. D, Peak dose of norepinephrine in µg/kg/min shown as box and scatterplots with trending lines between median peak doses. Baseline refers to the dose received at randomization. Detailed statistics can be found in Supplement Table 2 (http://links.lww.com/CCM/H704).

Figure 3.

S100-β levels over time and peak S100-β level between groups. A, S100-β levels on study days 0–3. Missing values were 0, 1, 23, 29 for days 0–3, respectively. B, Peak S100-β levels between dexmedetomidine and propofol/midazolam groups.

Figure 4.

Biomarker results between the two treatment groups. A, Interleukin-6 level level [pg/mL]. B, Acetylcholinesterase activity [U/g of hemoglobin (Hb)]. C, Butyrylcholinesterase [U/g of Hb]. D, Neurofilament light chain level [pg/mL]. Number of missing values are summarized in Supplement Table 7 (http://links.lww.com/CCM/H704).