Sedation depth and long-term mortality in mechanically ventilated critically ill adults: a prospective longitudinal multicentre cohort study

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Abstract

Purpose

To ascertain the relationship among early (first 48 h) deep sedation, time to extubation, delirium and long-term mortality.

Methods

We conducted a multicentre prospective longitudinal cohort study in 11 Malaysian hospitals including medical/surgical patients ( n = 259) who were sedated and ventilated ≥24 h. Patients were followed from ICU admission up to 28 days in ICU with 4-hourly sedation and daily delirium assessments and 180-day mortality. Deep sedation was defined as Richmond Agitation Sedation Score (RASS) ≤−3.

Results

The cohort had a mean (SD) age of 53.1 (15.9) years and APACHE II score of 21.3 (8.2) with hospital and 180-day mortality of 82 (31.7 %) and 110/237 (46.4 %). Patients were followed for 2,657 ICU days and underwent 13,836 RASS assessments. Midazolam prescription was predominant compared to propofol, given to 241 (93 %) versus 72 (28 %) patients ( P < 0.0001) for 966 (39.6 %) versus 183 (7.5 %) study days respectively. Deep sedation occurred in (182/257) 71 % patients at first assessment and in 159 (61 %) patients and 1,658 (59 %) of all RASS assessments at 48 h. Multivariable Cox proportional hazard regression analysis adjusting for a priori assigned covariates including sedative agents, diagnosis, age, APACHE II score, operative, elective, vasopressors and dialysis showed that early deep sedation was independently associated with longer time to extubation [hazard ratio (HR) 0.93, 95 % confidence interval (CI) 0.89–0.97, P = 0.003], hospital death (HR 1.11, 95 % CI 1.05–1.18, P < 0.001) and 180-day mortality (HR 1.09, 95 % CI 1.04–1.15, P = 0.002), but not time to delirium (HR 0.98, P = 0.23). Delirium occurred in 114 (44 %) of patients.

Conclusion

Irrespective of sedative choice, early deep sedation was independently associated with delayed extubation and higher mortality, and thus was a potentially modifiable risk in interventional trials.

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Most cited references 24

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Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial.

Timothy Girard, John Kress, Barry Fuchs … (2008)

Approaches to removal of sedation and mechanical ventilation for critically ill patients vary widely. Our aim was to assess a protocol that paired spontaneous awakening trials (SATs)-ie, daily interruption of sedatives-with spontaneous breathing trials (SBTs). In four tertiary-care hospitals, we randomly assigned 336 mechanically ventilated patients in intensive care to management with a daily SAT followed by an SBT (intervention group; n=168) or with sedation per usual care plus a daily SBT (control group; n=168). The primary endpoint was time breathing without assistance. Data were analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00097630. One patient in the intervention group did not begin their assigned treatment protocol because of withdrawal of consent and thus was excluded from analyses and lost to follow-up. Seven patients in the control group discontinued their assigned protocol, and two of these patients were lost to follow-up. Patients in the intervention group spent more days breathing without assistance during the 28-day study period than did those in the control group (14.7 days vs 11.6 days; mean difference 3.1 days, 95% CI 0.7 to 5.6; p=0.02) and were discharged from intensive care (median time in intensive care 9.1 days vs 12.9 days; p=0.01) and the hospital earlier (median time in the hospital 14.9 days vs 19.2 days; p=0.04). More patients in the intervention group self-extubated than in the control group (16 patients vs six patients; 6.0% difference, 95% CI 0.6% to 11.8%; p=0.03), but the number of patients who required reintubation after self-extubation was similar (five patients vs three patients; 1.2% difference, 95% CI -5.2% to 2.5%; p=0.47), as were total reintubation rates (13.8%vs 12.5%; 1.3% difference, 95% CI -8.6% to 6.1%; p=0.73). At any instant during the year after enrolment, patients in the intervention group were less likely to die than were patients in the control group (HR 0.68, 95% CI 0.50 to 0.92; p=0.01). For every seven patients treated with the intervention, one life was saved (number needed to treat was 7.4, 95% CI 4.2 to 35.5). Our results suggest that a wake up and breathe protocol that pairs daily spontaneous awakening trials (ie, interruption of sedatives) with daily spontaneous breathing trials results in better outcomes for mechanically ventilated patients in intensive care than current standard approaches and should become routine practice.

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Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials.

Stephan Jakob, Esko Ruokonen, R Michael Grounds … (2012)

Long-term sedation with midazolam or propofol in intensive care units (ICUs) has serious adverse effects. Dexmedetomidine, an α(2)-agonist available for ICU sedation, may reduce the duration of mechanical ventilation and enhance patient comfort. To determine the efficacy of dexmedetomidine vs midazolam or propofol (preferred usual care) in maintaining sedation; reducing duration of mechanical ventilation; and improving patients' interaction with nursing care. Two phase 3 multicenter, randomized, double-blind trials carried out from 2007 to 2010. The MIDEX trial compared midazolam with dexmedetomidine in ICUs of 44 centers in 9 European countries; the PRODEX trial compared propofol with dexmedetomidine in 31 centers in 6 European countries and 2 centers in Russia. Included were adult ICU patients receiving mechanical ventilation who needed light to moderate sedation for more than 24 hours (midazolam, n = 251, vs dexmedetomidine, n = 249; propofol, n = 247, vs dexmedetomidine, n = 251). Sedation with dexmedetomidine, midazolam, or propofol; daily sedation stops; and spontaneous breathing trials. For each trial, we tested whether dexmedetomidine was noninferior to control with respect to proportion of time at target sedation level (measured by Richmond Agitation-Sedation Scale) and superior to control with respect to duration of mechanical ventilation. Secondary end points were patients' ability to communicate pain (measured using a visual analogue scale [VAS]) and length of ICU stay. Time at target sedation was analyzed in per-protocol population (midazolam, n = 233, vs dexmedetomidine, n = 227; propofol, n = 214, vs dexmedetomidine, n = 223). Dexmedetomidine/midazolam ratio in time at target sedation was 1.07 (95% CI, 0.97-1.18) and dexmedetomidine/propofol, 1.00 (95% CI, 0.92-1.08). Median duration of mechanical ventilation appeared shorter with dexmedetomidine (123 hours [IQR, 67-337]) vs midazolam (164 hours [IQR, 92-380]; P = .03) but not with dexmedetomidine (97 hours [IQR, 45-257]) vs propofol (118 hours [IQR, 48-327]; P = .24). Patients' interaction (measured using VAS) was improved with dexmedetomidine (estimated score difference vs midazolam, 19.7 [95% CI, 15.2-24.2]; P < .001; and vs propofol, 11.2 [95% CI, 6.4-15.9]; P < .001). Length of ICU and hospital stay and mortality were similar. Dexmedetomidine vs midazolam patients had more hypotension (51/247 [20.6%] vs 29/250 [11.6%]; P = .007) and bradycardia (35/247 [14.2%] vs 13/250 [5.2%]; P < .001). Among ICU patients receiving prolonged mechanical ventilation, dexmedetomidine was not inferior to midazolam and propofol in maintaining light to moderate sedation. Dexmedetomidine reduced duration of mechanical ventilation compared with midazolam and improved patients' ability to communicate pain compared with midazolam and propofol. More adverse effects were associated with dexmedetomidine. clinicaltrials.gov Identifiers: NCT00481312, NCT00479661.

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Incidence, risk factors and consequences of ICU delirium.

Sébastien Ouimet, Brian P Kavanagh, Stewart B. Gottfried … (2007)

Delirium in the critically ill is reported in 11-80% of patients. We estimated the incidence of delirium using a validated scale in a large cohort of ICU patients and determined the associated risk factors and outcomes. Prospective study in a 16-bed medical-surgical intensive care unit (ICU). 820 consecutive patients admitted to ICU for more than 24 h. Tools used were: the Intensive Care Delirium Screening Checklist for delirium, Richmond Agitation and Sedation Scale for sedation, and Numerical Rating Scale for pain. Risk factors were evaluated with univariate and multivariate analysis, and factors influencing mortality were determined using Cox regression. Delirium occurred in 31.8% of 764 patients. Risk of delirium was independently associated with a history of hypertension (OR 1.88, 95% CI 1.3-2.6), alcoholism (2.03, 1.2-3.2), and severity of illness (1.25, 1.03-1.07 per 5-point increment in APACHE II score) but not with age or corticosteroid use. Sedatives and analgesics increased the risk of delirium when used to induce coma (OR 3.2, 95% CI 1.5-6.8), and not otherwise. Delirium was linked to longer ICU stay (11.5+/-11.5 vs. 4.4+/-3.9 days), longer hospital stay (18.2+/-15.7 vs. 13.2+/-19.4 days), higher ICU mortality (19.7% vs. 10.3%), and higher hospital mortality (26.7% vs. 21.4%). Delirium is associated with a history of hypertension and alcoholism, higher APACHE II score, and with clinical effects of sedative and analgesic drugs.

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Author and article information

Contributors

Yahya Shehabi: +61-2-93824721 , +61-4-19296986 , +61-2-93824870 , y.shehabi@unsw.edu.au

Journal

Journal ID (nlm-ta): Intensive Care Med

Journal ID (iso-abbrev): Intensive Care Med

Title: Intensive Care Medicine

Publisher: Springer-Verlag (Berlin/Heidelberg )

ISSN (Print): 0342-4642

ISSN (Electronic): 1432-1238

Publication date (Electronic): 24 January 2013

Publication date PMC-release: 24 January 2013

Publication date (Print): May 2013

Volume: 39

Issue: 5

Pages: 910-918

Affiliations

[ ]Department of Intensive Care, University New South Wales Clinical School, The Prince of Wales Hospital, Barker St., Randwick, NSW 2031 Australia

[ ]Department of Anesthesiology, Faculty of Medicine, University of Malaya, Lembah Pantai, 50603 Kuala Lumpur, Malaysia

[ ]National Heart Institute (Institut Jantung Negara), 145 Jalan Tun Razak, 50400 Kuala Lumpur, Malaysia

[ ]Department of Anesthesia and Intensive Care, Hospital Melaka, Jalan Mufti Hj Khalil, 75400 Melaka, Malaysia

[ ]Hospital Raja Perempuan Zainab II Kota Bahru–HKB, Kelantan, Malaysia

[ ]Department of Anesthesia and Intensive Care, General ICU, Kuala Lumpur General Hospital, Jalan Pahang, 50586 Kuala Lumpur, Malaysia

[ ]Department of Anesthesiology and Intensive Care, Hospital Queen Elizabeth, 88586 Kota Kinabalu, Sabah Malaysia

[ ]Department of Anesthesiology, School of Medicine, Hospital University Sains Malaysia, Health Campus, 16150 Kota Bahru, Kelantan Malaysia

[ ]Department of Anesthesiology and Intensive Care, Sarawak General Hospital, Jalan Hospital, 93586 Kuching, Sarawak Malaysia

[ ]Hospital Sultanah Bahiyah, Alor Setar, HAS, Kedah, Malaysia

[ ]ICU Selatan, 2nd Floor, Hospital Sultanah Aminah, Jalan Persiaran Abu Bakar, Johor Bahru, Johor Malaysia

[ ]Penang General Hospital, PGH, Penang, Malaysia

[ ]Australian New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine Monash University, Melbourne, Australia

[ ]University New South Wales, Prince of Wales Hospital, Sydney, Australia

Article

Publisher ID: 2830

DOI: 10.1007/s00134-013-2830-2

PMC ID: 3625407

PubMed ID: 23344834

SO-VID: c68d2473-2ec2-425e-9cf0-1afdf7e1cf70

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

History

Date received : 4 August 2012

Date accepted : 22 December 2012

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ScienceOpen disciplines: Emergency medicine & Trauma

Keywords: sedation depth,mechanical ventilation,delirium,critically ill,mortality

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ScienceOpen disciplines: Emergency medicine & Trauma

Keywords: sedation depth, mechanical ventilation, delirium, critically ill, mortality

Sedation depth and long-term mortality in mechanically ventilated critically ill adults: a prospective longitudinal multicentre cohort study

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Irish Journal of Paramedicine

Most cited references 24

Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial.

Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials.

Incidence, risk factors and consequences of ICU delirium.

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