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

Pratik P Pandharipande12, Robert D Sanders3*, Timothy D Girard456, Stuart McGrane12, Jennifer L Thompson7, Ayumi K Shintani7, Daniel L Herr8, Mervyn Maze9, E Wesley Ely456 and the MENDS investigators

Author Affiliations

1 Anesthesiology Service, VA TN Valley Health Care System, 1310 24th Avenue South, Nashville, TN 37212-2637, USA

2 Department of Anesthesiology, Division of Critical Care, Vanderbilt University School of Medicine; 324 MAB, Nashville, TN 37212-1120, USA

3 Department of Leucocyte Biology & Magill Department of Anaesthetics, Intensive Care and Pain Medicine, Imperial College London, Chelsea & Westminster Hospital, 369 Fulham Road, London, SW10 9NH, UK

4 Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine; T-1218 MCN, Nashville, TN 37232-2650, USA

5 Center for Health Services Research, Vanderbilt University School of Medicine; 6th Floor MCE, Suite 6100, Nashville, TN 37232-8300, USA

6 Veterans Affairs Tennessee Valley Geriatric Research, Education, and Clinical Center; 1310 24th Avenue South, Nashville, TN 37212-2637, USA

7 Department of Biostatistics, Vanderbilt University School of Medicine; S-2323 MCN, Nashville, TN 37232-2158, USA

8 Department of Surgery and Surgical Critical Care, Washington Hospital Center; 110 Irving St NW, Room 4B42, Washington, DC 20010, USA

9 Department of Anesthesiology and Perioperative Care, University of California San Francisco; 521 Parnassus Avenue, C455, San Francisco, CA 94143-0648, USA

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Critical Care 2010, 14:R38  doi:10.1186/cc8916


See related commentary by Kress, http://ccforum.com/content/14/3/164 and related letter by Quintin, http://ccforum.com/content/14/4/429

Published: 16 March 2010

Abstract

Introduction

Benzodiazepines 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.

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.