Effect of dexmedetomidine versus lorazepam on outcome in patients with sepsis: an a priori-designed analysis of the MENDS randomized controlled trial

Abstract

IntroductionBenzodiazepines and α2 adrenoceptor agonists exert opposing effects on innate immunity and mortality in animal models of infection. We hypothesized that sedation with dexmedetomidine (an α2 adrenoceptor agonist), as compared with lorazepam (a benzodiazepine), would provide greater improvements in clinical outcomes among septic patients than among non-septic patients.MethodsIn this a priori-determined subgroup analysis of septic vs non-septic patients from the MENDS double-blind randomized controlled trial, adult medical/surgical mechanically ventilated patients were randomized to receive dexmedetomidine-based or lorazepam-based sedation for up to 5 days. Delirium and other clinical outcomes were analyzed comparing sedation groups, adjusting for clinically relevant covariates as well as assessing interactions between sedation group and sepsis.ResultsOf the 103 patients randomized, 63 (31 dexmedetomidine; 32 lorazepam) were admitted with sepsis and 40 (21 dexmedetomidine; 19 lorazepam) without sepsis. Baseline characteristics were similar between treatment groups for both septic and non-septic patients. Compared with septic patients who received lorazepam, the dexmedetomidine septic patients had 3.2 more delirium/coma-free days (DCFD) on average (95% CI for difference, 1.1 to 4.9), 1.5 (-0.1, 2.8) more delirium-free days (DFD) and 6 (0.3, 11.1) more ventilator-free days (VFD). The beneficial effects of dexmedetomidine were more pronounced in septic patients than in non-septic patients for both DCFDs and VFDs (P-value for interaction = 0.09 and 0.02 respectively). Additionally, sedation with dexmedetomidine, compared with lorazepam, reduced the daily risk of delirium [OR, CI 0.3 (0.1, 0.7)] in both septic and non-septic patients (P-value for interaction = 0.94). Risk of dying at 28 days was reduced by 70% [hazard ratio 0.3 (0.1, 0.9)] in dexmedetomidine patients with sepsis as compared to the lorazepam patients; this reduction in death was not seen in non-septic patients (P-value for interaction = 0.11).ConclusionsIn this subgroup analysis, septic patients receiving dexmedetomidine had more days free of brain dysfunction and mechanical ventilation and were less likely to die than those that received a lorazepam-based sedation regimen. These results were more pronounced in septic patients than in non-septic patients. Prospective clinical studies and further preclinical mechanistic studies are needed to confirm these results.Trial RegistrationNCT00095251.

Incidence and risk factors for delirium development in ICU patients - a prospective observational study

“…Especially benzodiazepines (act through γ-aminobutyric acid, GABA A receptors) pose great risk for developing delirium.They have been associated with delirium in several studies across multiple ICU populations. Three randomized trials (MENDS, SEDCOM and Maldonado´s study) comparing benzodiazepines to an alternative sedative (dexmedetomidine) demonstrate significantly lower prevalence of delirium, more days alive and days free of delirium or coma with dexmedetomidine [43][44][45] . It is time to change the practise of sedation.…”

“…Others are modifiable, such as minimizing the drug-induced sedation and the duration of artificial ventilation. The use of sedation may disturb neurotransmission in the brain (the use of benzodiazepines, propofol, or morphine) and was shown to be a risk factor in previous studies 16,21,[41][42][43] . Especially benzodiazepines (act through γ-aminobutyric acid, GABA A receptors) pose great risk for developing delirium.They have been associated with delirium in several studies across multiple ICU populations.…”

Pharmacological and Nonpharmacological Management of Delirium in Critically Ill Patients

“…Sedation with dexmedetomidine resulted in more days alive without delirium or coma (p00.01) and lower prevalence of coma (p<0.001) than sedation with lorazepam. A subgroup analysis of the database from the study, which was planned a priori, demonstrated that sedation with dexmedetomidine reduced the daily risk of delirium as well (p00.02) [132] (Fig. 1a), and this effect was most prominent in patients with severe sepsis.…”

“…Note that both groups start with 60% prevalence of delirium in keeping with most cohorts of mechanically ventilated patients, and then there is a large difference in delirium prevalence throughout the remainder of the study period. Adapted from Pandharipande, et al [132]. (b) In the Safety and Efficacy of Dexmedetomidine Compared with Midazolam (SEDCOM) trial comparing dexmedetomidine to midazolam for sedation of mechanically ventilated patients, the prevalence of delirium in dexmedetomidine-treated patients was significantly less than midazolam-treated patients (54% vs 76.6%; p<0.001).…”

Delirium in the elderly in intensive care units: an integrative literature review

“…Predisposing and precipitating risk factors for the development of delirium in the elderly in ICU , sleep disturbances 5,9,12,19 , invasive devices 9,13 and environmental characteristics of the ICU as artificial lighting, noise, family isolation. 7,9 The delirium association with the aggravation of chronic Comorbidities that culminate with hepatic dysfunction, cardiovascular and renal has been described in five studies.…”