Objective: To assess the feasibility and safety of delivering early goal-directed sedation compared with standard sedation.
Design: Pilot prospective, multicenter, randomized, controlled trial.
Setting: Six ICUs.
Patients: Critically ill adults mechanically ventilated for greater than 24 hours.
Interventions: Patients randomized to early goal-directed sedation received a dexmedetomidine-based algorithm targeted to light sedation (Richmond Agitation Sedation Score of –2 to 1). Patients randomized to standard sedation received propofol and/or midazolam-based sedation as clinically appropriate.
Measurements and Main Results: The main feasibility outcomes were time to randomization and proportion of Richmond Agitation Sedation Score assessments in the first 48 hours in the light and deep sedation range. Safety outcomes were delirium-free days, vasopressor and physical restraints use, and device removal. Randomization occurred within a median (interquartile range) of 1.1 hours (0.46–1.9) after intubation or ICU admission for out of ICU intubation. Patients in the early goal-directed sedation (n = 21) mean (SD) Acute Physiology and Chronic Health Evaluation II score was 20.2 (6.2) versus 18.6 (8.8; p = 0.53) in the standard sedation (n = 16). A significantly higher proportion of patients was lightly sedated on days 1, 2, and 3 (12/19 [63.2%], 19/21 [90.5%], and 18/20 [90%] vs 2/14 [14.3%], 8/15 [53.3%], and 9/15 [60%]; p = 0.005, 0.011, 0.036) and more Richmond Agitation Sedation Scale assessments between (–2 and 1), in the first 48 hours (203/307 [66%] versus (74/197 [38%]; p = 0.01) in the early goal-directed sedation versus standard sedation, respectively. Early goal-directed sedation patients received midazolam on 6 of 173 (3.5%) versus 4 of 114 (3.5%) standard sedation patient-days when dexmedetomidine was given. Propofol was given to 16 of 21 (76%) of early goal-directed sedation versus 16 of 16 (100%) of standard sedation patients (p = 0.04). Early goal-directed sedation patients had 101 of 175 (58%) versus 54 of 114 (47%; p = 0.27) delirium-free days and required significantly less physical restraints 1 (5%) versus 5 (31%; p = 0.03) than standard sedation patients. There were no differences in vasopressor use and self-extubation.
Conclusions: Delivery of early goal-directed sedation was feasible, appeared safe, achieved early light sedation, minimized benzodiazepines and propofol, and decreased the need for physical restraints. The findings of this pilot study justify further investigation of early goal-directed sedation.
1University New South Wales, Clinical School of Medicine, Director Intensive Care Research, Prince of Wales Hospital, Randwick, New South Wales, Australia.
2University of Melbourne, Faculty of Medicine, School of Public Health and Preventive Medicine, Monash University, Director Intensive Care Research, Austin Hospital, Heidelberg, Australia.
3Australian New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia.
4Australian Defence Force and Burns, Trauma and Critical Care Research Centre, Royal Brisbane and Women’s Hospital, University of Queensland, Queensland, Australia.
5Department of Intensive Care Services, Prince of Wales Hospital, Randwick, Australia.
6Department of Critical Care Medicine, Auckland City Hospital, Auckland, New Zealand.
7Department of Intensive Care Medicine, University of Sydney, Sydney Medical School Nepean, New South Wales, Australia.
8Royal Perth Hospital, School of Medicine and Pharmacology and School of Population Health, University of Western Australia, Perth, Australia.
9Department of Intensive Care, Sydney Nursing School, University of Sydney, Nepean Hospital, New South Wales, Australia.
*See also p. 2053.
Drs. Shehabi, Bellomo, Reade, Bailey, and Ms. Howe had full access to the data and participated in the analysis and interpretation of the data. Drs. Shehabi, Bellomo, Reade, Webb, Seppelt, McArthur, Bass, and Weisbrodt participated in the study concept and design. Drs. Bailey, Howe, Bass, Weisbrodt, Murray participated in the acquisition of data and data management. Drs. Bailey, Shehabi, Bellomo, Reade, Seppelt, Webb, Murray, and McArthur participated in analysis and interpretation of data. Drs. Shehabi, Bellomo, Seppelt, Reade, Webb and McArthur participated in drafting of the manuscript. Drs. Shehabi, Bellomo, Reade, Bailey, Seppelt, Webb, McArthur, Bass, Murray and Weisbrodt participated in critical review and intellectual input. This study was conducted in collaboration with the Australian New Zealand Intensive Care Research Centre (ANZIC RC) and the department of epidemiology and preventive medicine of the faculty of medicine at Monash University, Melbourne, Australia. Hospira and its employees had no input into the design, protocol, study conduct, data collection, data analysis, manuscript preparation, review and submission. However, Hospira, Melbourne, Australia, provided the study drug dexmedetomidine at no cost to study sites.
Supported, in part, by an unrestricted Grant-In-Aid from Hospira, Lake Forest, IL. Dr. Shehabi has received unrestricted Grant-In-Aid research grants from Hospira Inc. (Lake Forest, IL); research grants from Roche Diagnostics and Thermofisher Scientific; competitive research funding grants from National Health and Medical Research Council, Australia. Dr. Shehabi's research department has received payment for article preparation for being part of SEDCOM delirium manuscript review 2009; and speakers’ honoraria and consulting fee from Hospira and Roche Diagnostics. He was on an advisory boards for Hospira and GSK and has received payment from GSK for the development of educational material approved by College of Intensive Care Medicine of ANZ. Dr. Reade has received a consulting fee and research grants from Hospira. Dr. McArthur has received grant support, travel reimbursements, and provisions for writing assistance from Hospira Australia. Dr. Seppelt was on an advisory board in Intensive Care supported by Hospira; has received competitive research funding grants from National Health and Medical Research Council, Australia; and has received payment for the development of educational presentations from Asklepios Medical Education. Dr. Webb has consulted for Aalix Healthcare Services Consulting, Ibis Biosciences, Astra Zeneca, Jansen Cilag, and has received grant support from Fresenius Kabi. The remaining authors have not disclosed any potential conflicts of interest.
Participating centers and principal investigators are listed in the Appendix 1.
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