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Sedation Intensity in the First 48 Hours of Mechanical Ventilation and 180-Day Mortality

A Multinational Prospective Longitudinal Cohort Study*

Shehabi, Yahya, PhD, FCICM, FANZCA, EMBA1,2; Bellomo, Rinaldo, MD (Hons), FRACP, FCICM3,4,5; Kadiman, Suhaini, MD, M.MED6; Ti, Lian Kah, MBBS, Mmed7; Howe, Belinda, RN, BN8; Reade, Michael C., MBBS, MPH, Dphil, FCICM9; Khoo, Tien Meng, MBBS, MRCP, EDIC10; Alias, Anita, MD, MMed(Anaesth)11; Wong, Yu-Lin, FANZCA, MMed (ICM)12; Mukhopadhyay, Amartya, FRCP, MPH7; McArthur, Colin, MBChB, FANZCA, FCICM13; Seppelt, Ian, MBBS, BSc (Med), FANZCA, FCICM14; Webb, Steven A., MPH, PhD, FCICM8,15; Green, Maja, PhD, MSc, BSc (Hons)1; Bailey, Michael J., PhD, MSc (statistics), BSc (Hons)1,8 for the Sedation Practice in Intensive Care Evaluation (SPICE) Study Investigators and the Australian and New Zealand Intensive Care Society Clinical Trials Group

doi: 10.1097/CCM.0000000000003071
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Objectives: In the absence of a universal definition of light or deep sedation, the level of sedation that conveys favorable outcomes is unknown. We quantified the relationship between escalating intensity of sedation in the first 48 hours of mechanical ventilation and 180-day survival, time to extubation, and delirium.

Design: Harmonized data from prospective multicenter international longitudinal cohort studies

Setting: Diverse mix of ICUs.

Patients: Critically ill patients expected to be ventilated for longer than 24 hours.

Interventions: Richmond Agitation Sedation Scale and pain were assessed every 4 hours. Delirium and mobilization were assessed daily using the Confusion Assessment Method of ICU and a standardized mobility assessment, respectively.

Measurements and Main Results: Sedation intensity was assessed using a Sedation Index, calculated as the sum of negative Richmond Agitation Sedation Scale measurements divided by the total number of assessments. We used multivariable Cox proportional hazard models to adjust for relevant covariates. We performed subgroup and sensitivity analysis accounting for immortal time bias using the same variables within 120 and 168 hours. The main outcome was 180-day survival. We assessed 703 patients in 42 ICUs with a mean (SD) Acute Physiology and Chronic Health Evaluation II score of 22.2 (8.5) with 180-day mortality of 32.3% (227). The median (interquartile range) ventilation time was 4.54 days (2.47–8.43 d). Delirium occurred in 273 (38.8%) of patients. Sedation intensity, in an escalating dose-dependent relationship, independently predicted increased risk of death (hazard ratio [95% CI], 1.29 [1.15–1.46]; p < 0.001, delirium hazard ratio [95% CI], 1.25 [1.10–1.43]), p value equals to 0.001 and reduced chance of early extubation hazard ratio (95% CI) 0.80 (0.73–0.87), p value of less than 0.001. Agitation level independently predicted subsequent delirium hazard ratio [95% CI], of 1.25 (1.04–1.49), p value equals to 0.02. Delirium or mobilization episodes within 168 hours, adjusted for sedation intensity, were not associated with survival.

Conclusions: Sedation intensity independently, in an ascending relationship, predicted increased risk of death, delirium, and delayed time to extubation. These observations suggest that keeping sedation level equivalent to a Richmond Agitation Sedation Scale 0 is a clinically desirable goal.

1Critical Care and Perioperative Services, Monash University and Monash Health, Melbourne, VIC, Australia.

2Clinical School, University New South Wales, Sydney, NSW, Australia.

3Faculty of Medicine, University of Melbourne, Melbourne, VIC, Australia.

4Faculty of Medicine, Australian New Zealand Intensive Care Research Centre, Monash University, Melbourne, VIC, Australia.

5Department of Intensive Care, The Austin Hospital, Melbourne, VIC, Australia.

6Department of Anaesthesiology and Intensive Care, National Heart Institute, Kuala Lumpur, Malaysia.

7Yong Loo Lin School of Medicine, National University of Singapore, National University Hospital, Singapore.

8Australian New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia.

9University of Queensland, Royal Brisbane and Women’s Hospital, Herston, QLD, Australia.

10Department of Anesthesiology and Intensive Care, Hospital Queen Elizabeth, Sabah, Malaysia.

11Department of Anaesthesia and Intensive Care, Hospital Melaka - Jalan Mufti Hj Khalil, Melaka, Malaysia.

12Department of Anaesthesia, Tan Tock Seng Hospital, Singapore.

13Department of Critical Care Medicine, University of Auckland, Auckland City Hospital, Auckland, New Zealand.

14Department of Intensive Care Medicine, University of Sydney, Sydney Medical School, Nepean, NSW, Australia.

15Department of Intensive Care, St John of God Hospital, Subiaco, Perth, WA, Australia.

*See also p. 1003.

All authors approved the version submitted. Dr. Shehabi contributed to the study concept and design, data interpretation, article drafting, and submission. Dr. Bellomo contributed to the study concept and design, article review. Dr. Bailey contributed to study concept and design, statistical analyses, and article review. Drs. Shehabi, Bellomo, and Bailey accept responsibility for the integrity and the accuracy of all the data. Dr. Green contributed to data analysis and interpretation, statistical analyses, article review, and formatting. Ms. Howe contributed to study concept, data interpretation, and article review. All authors contributed to acquisition and interpretation of data, article review, and critique. All authors approved the final submitted article. The Sedation Practice in Intensive Care Evaluation Program was managed by the Australian and New Zealand Intensive Care Research Centre.

A full list of Sedation Practice in Intensive Care Evaluation (SPICE) Study Investigators is listed in Appendix 1.

The parent SPICE studies were supported by an unrestricted research grant from Pfizer (Hospira, Lake forest, IL), Grant-in-Aide Program.

Dr. Shehabi declares unrestricted research and educational grant support from Pfizer (Hospira, Lake Forest, IL), Orion Pharma – Helsinki Finland in support of the Sedation Practice in Intensive Care Evaluation Program. Dr. Reade declares unrestricted research and educational grant support from Pfizer (Hospira, Melbourne, VIC) Australia. Dr. McArthur disclosed project grant funding from the Health Research Council of New Zealand for a prospective, randomized clinical trial of intensive care sedation. The remaining authors have disclosed that they do not have any potential conflicts of interest.

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