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

Pratik P Pandharipande, Robert D Sanders, Timothy D Girard, Stuart McGrane, Jennifer L Thompson, Ayumi K Shintani, Daniel L Herr, Mervyn Maze, E Wesley Ely, MENDS investigators, Pratik P Pandharipande, Robert D Sanders, Timothy D Girard, Stuart McGrane, Jennifer L Thompson, Ayumi K Shintani, Daniel L Herr, Mervyn Maze, E Wesley Ely, MENDS investigators

Abstract

Introduction: Benzodiazepines and alpha2 adrenoceptor agonists exert opposing effects on innate immunity and mortality in animal models of infection. We hypothesized that sedation with dexmedetomidine (an alpha2 adrenoceptor agonist), as compared with lorazepam (a benzodiazepine), would provide greater improvements in clinical outcomes among septic patients than among non-septic patients.

Methods: In 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.

Results: Of 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).

Conclusions: In 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 registration: NCT00095251.

Figures

Figure 1
Figure 1
Forest plot demonstrating interactions between sepsis and the effect of sedative group on delirium/coma-free days, delirium-free days, coma-free days, and ventilator-free days. For each outcome, the adjusted difference in the means between the dexmedetomidine group and lorazepam group is presented, first for the septic patients (heavy circle) and then for the non-septic patients (heavy triangle), along with 95% confidence intervals (CI) for the difference. Differences, CIs and P values were calculated using bootstrap multiple linear regression, adjusting for age, the acute physiology component of the Acute Physiology and Chronic Health Evaluation (APACHE) II score at enrollment, administration of drotrecogin alfa (activated), treatment group, sepsis, and treatment group by sepsis interaction. If the difference in means is greater than 0, it reflects an improved outcome with dexmedetomidine; if less than 0, then patients on lorazepam had a better outcome. We considered a P value for interaction less than 0.15 to indicate that the effect of sedative group on the outcome in question was different for septic patients than for non-septic patients. A P value for interaction of 0.15 or more, alternatively, indicated that the effect of sedation group on outcomes was the same for all patients, regardless of sepsis.
Figure 2
Figure 2
Prevalence of delirium while on study drug. The top panel demonstrates that, among all patients, those sedated with dexmedetomidine (DEX) had a 70% lower likelihood of having delirium on any given day compared with patients sedated with lorazepam (LZ). Sepsis did not modify this relation (adjusted P for interaction = 0.94), meaning that dexmedetomidine reduced the risk of developing delirium whether patients had sepsis (lower panel) or not. * Number of patients assessed denotes the number of patients who were alive, in the ICU, and not comatose (Richmond Agitation-Sedation Scale (RASS)-3 or lighter) and are therefore assessable for delirium. Percentages of patients alive and without coma, but with delirium, are represented with black bars if on lorazepam and gray bars if on dexmedetomidine.
Figure 3
Figure 3
Kaplan-Meier curve showing probability of survival during the first 28 days according to treatment group, among patients with sepsis. Dexmedetomidine decreased the probability of dying within 28 days by 70%; this beneficial effect was not seen in patients who were not septic (P value for interaction = 0.11 implying an interaction between sepsis and the treatment groups).

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