Share this article on:

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)1,8for 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
Feature Articles
Editor's Choice

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.

For information regarding this article, E-mail: yahya.shehabi@monashhealth.org; y.shehabi@unsw.edu.au

The management of pain, agitation, sedation, delirium, and mobilization represents a major challenge in the care of critically ill patients. Guidelines and best practice recommendations have been proposed to provide guidance to clinicians on their management (1 , 2). These recommendations, however, are based on studies reporting potential benefits in relation to short-term endpoints, such as ventilation time and ICU length of stay, rather than patient-centered endpoints such as long-term survival (3).

In this regard, more recently, depth of sedation, in the first 48 hours following mechanical ventilation, has been reported to predict mortality up to 2 years, independent of severity of illness and other potential confounders, in different cohorts of critically ill patients ventilated for longer than 24 hours (4–7).

Despite such promising observations, there continues to be genuine uncertainty and controversy about the association of sedation depth, among other determinants of sedation practice, and long-term outcomes such as mortality (3). This is, at least in part, because elements of sedation practice (agitation, pain control, delirium, and timing and intensity of mobilization) have not previously been measured simultaneously to exclude their confounding interactions with sedation.

From a methodological point of view, the validated Richmond Agitation Sedation Scale (RASS) (8) scoring system measures depth of sedation (negative values) and agitation (positive values) on a single scale. As there is no universal definition of intensity of sedation, light sedation has been arbitrarily and conveniently categorized as a RASS score of –2 to +1 (9). Such definition, however, may confound patients who are moderately sedated (–2), calm (0) with those who are mildly agitated (+1) and considers them as equivalent, an approach that lacks clinical logic. Similarly, deep sedation has been categorized as a RASS score of –3 to –5 (10). This approach classifies patients with a RASS score of –3 (moderate sedation) as equivalent to those with a RASS score of –4 and –5 (deep or unrousable sedation). Furthermore, RASS scores can vary widely, over a short period of time, making it impossible to choose a representative score for a particular time period. The dynamic nature of changes in sedation and agitation makes current methodology for assessment of sedation and agitation problematic and imperfect. As a consequence, evaluation of these countervailing variables with arbitrarily defined categories of (deep vs light vs agitated state) can obscure real relationships with outcomes. Such relationships can specifically relate to varying levels of sedation depth or agitation at different times in the same patient. In contrast, evaluating sedation and agitation separately should logically make these relationships more apparent.

In order to address the above issues, we used data collected in previously conducted prospective international longitudinal cohort studies to present an outcome-based characterization of sedation depth, using the RASS scale, to define the “intensity of sedation” measured by a tool called “the Sedation Index (SI).” Considering the high prevalence of deep sedation in contrast to agitation, we focused on the utility of SI to provide a measure that defines sedation intensity on a continuous scale taking into account the time dimension and the level of sedation delivered. Accordingly, we quantified the relationship between sedation intensity in the first 48 hours following mechanical ventilation and 180-day mortality, time to extubation, subsequent delirium, and ICU and hospital length of stay.

Back to Top | Article Outline

METHODS

Study Design and Patients

We performed multicenter international longitudinal observational studies in 42 ICUs in Australia and New Zealand (ANZ) (4), Malaysia (5), and Singapore between 2010 and 2013 as part of the Sedation Practice in Intensive Care Evaluation investigational program.

Patients were enrolled at admission to ICU if they were expected to be sedated and mechanically ventilated for more than 24 hours. The full inclusion/exclusion criteria were presented in the primary publication (4). We used a harmonized protocol and identical data points that were centrally managed and combined into one dataset. Monash University’s Human Research Ethics Committee and individual sites granted approval for the study.

We excluded patients with a hospital stay of less than 48 hours, including death. The primary outcome for this study was patient survival to 180 days from ICU admission, whereas secondary outcomes included time to extubation and subsequent delirium (Positive Confusion Assessment Method of ICU [CAM-ICU] beyond 48 hr), ICU and hospital length of stay. Tertiary outcomes included the administration of sedative and analgesic agents during the study period.

We monitored, every 4 hours until ICU discharge or day 28 (whichever came first), sedation depth and agitation level using the RASS scale (8) and pain intensity using the Numerical Rating Scale (NRS) or the critical care pain observational tool for adult patients (11). Pain intensity was recorded as yes/no (NRS ≥ 3). Daily delirium and mobilization episodes until discharge from ICU or day 28 were assessed by specifically trained staff at each hospital using the CAM-ICU (12) and daily recording of active mobilization episodes (at least setting at the bedside) in ICU according to a standardized descriptive mobility assessment. Delirium was only assessed when the RASS score was between –2 and +1 to reduce the number of false-positive delirium assessments (8).

The principal exposure variable of interest was sedation intensity during the first 48 hours of mechanical ventilation in ICU as determined by RASS scores. To use their ordinal properties, RASS scores were divided into sedation (RASS –1 to –5) and agitation components (RASS 1–4). Sedation intensity as measured by the SI was defined as the sum of negative RASS scores divided by the number of RASS measurements. SI construct, external and criterion validity were established using Pearson Correlation coefficients and Cronbach’s alpha (Tables S1 and S2, Supplemental Digital Content 1, http://links.lww.com/CCM/D358). To account for missing RASS data, a sensitivity analysis using multiple imputation was performed (Table S3, Supplemental Digital Content 1, http://links.lww.com/CCM/D358).

Back to Top | Article Outline

Statistical Analysis

In the absence of any previous literature pertaining to the SI, a conservative SD was estimated from the range of possible values (0–5) and a ratio of survivors to nonsurvivors of approximately 2:1, with 703 patients; this study had greater than 95% power (two-sided p = 0.05) to detect a 0.5 unit difference (33% of one SD) in sedation intensity score as measured by SI between survivors and nonsurvivors.

All data were initially assessed for normality. The relationships between SI and time to event outcomes occurring after the 48-hour exposure period (death, extubation, and delirium) were determined using multivariable Cox proportional hazard regression with patients censored at 180 days (or last known date alive for those lost to follow-up) and hospital discharge, respectively. Proportionality assumptions and model discrimination were determined using Schoenfeld residuals and Harrell’s C-index, respectively, with results presented as hazard ratios (HRs) (95% CI). In accordance with our previous work (4), all multivariate models were adjusted for age, gender, weight, patient severity (Acute Physiology and Chronic Health Evaluation [APACHE] II), admission source, surgical status, admission status (elective or emergency), country, and diagnosis along with other previously defined exposure variables of interest (mobilization, pain, and agitation). Heterogeneity between individual sites was controlled for by nesting patients within sites and treating sites as a random effect. First order interactions between SI and all other variables were assessed for significance.

Further analysis of the above relationships included sensitivity analysis using linear regression and linear mixed modeling, linearity and dose response using LOcal regrESSion (LOWESS) smoothers, and log rank tests and subgroup analysis using Cox proportional Hazard regression model. Subgroup and sensitivity analyses, accounting for immortal time bias, were conducted considering exposure windows of 120 and 168 hours, with the number of mobilization, delirium, and pain episodes treated as continuous events.

Statistical methods are described in the supplemental data (Supplemental Digital Content 1, http://links.lww.com/CCM/D358). A two-sided p value of 0.05 indicated statistical significance. All analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC).

Back to Top | Article Outline

RESULTS

The total number of patients in the combined dataset was 710, from ANZ (n = 251), Malaysia (n = 259), and Singapore (n = 200). We excluded seven (1%) patients who were discharged or died within the principal exposure period (first 48 hr) leaving a cohort of 703 patients for the primary survival analysis. Analysis at 120 and 168 hours included 674 and 628 patients, respectively. Thirty-eight patients were lost to follow-up resulting in 665 patients with complete 180-day mortality information (Fig. 1).

Figure 1

Figure 1

The baseline demographics and interventions during the study period for all patients, survivors, and nonsurvivors are shown in Table 1.

TABLE 1

TABLE 1

Back to Top | Article Outline

Sedation Assessment

The overall number of RASS assessments conducted up to 168 hours was 21,273 with 6,811 in the first 48 hours. There was no difference in the average number of RASS measurements recorded in the first 48 hours between survivors after 48 hours 9.6 (1.9) and nonsurvivors 9.5 (1.8) (p = 0.41).

Back to Top | Article Outline

Predictors of 180-Day Mortality

Using an exposure window of the first 48 hours, Cox proportional hazard modeling, the SI in the first 48 hours (but not pain, agitation measured as an index, delirium, or mobilization) was a significant independent predictor of increased risk of death at 180-day HR (95% CI) of 1.29 (1.15–1.46), p value of less than 0.001 (Table 2). Furthermore, when considering the predicted risk of death at 180 days derived from the multivariable logistic regression model, there was an escalating dose-dependent relationship between SI and risk of death (Fig. S1, Supplemental Digital Content 1, http://links.lww.com/CCM/D358). The Tertiles of SI also showed a stepped-up increase in 180-day mortality (log rank p < 0.001) (Fig. 2A).

TABLE 2

TABLE 2

Figure 2

Figure 2

Other significant predictors of increased risk of death at 180-day included age and renal replacement therapy in the first 48 hours, with a HR (95% CI) of 1.02 (1.01–1.03), p value of less than 0.001 and 1.47 (1.07–2.03), p value equals to 0.02, respectively. These results were supported by similar findings using logistic regression to determine 180-day mortality (Table S5, Supplemental Digital Content 1, http://links.lww.com/CCM/D358).

When considering subgroup analysis (age, APACHE II, diagnosis, country, use of fentanyl, midazolam, morphine, propofol or dexmedetomidine, elective or emergency surgery) for 180-day mortality, the greatest heterogeneity was found for patient diagnosis (p = 0.03) with SI having the strongest relationship in sepsis patients HR (95% CI) of 1.68 (1.30–2.16) (Fig. 3).

Figure 3

Figure 3

Expanding the exposure window to 120 or 168 hours, using Cox proportional hazard modeling, showed consistent result for SI and increased 180-day mortality with HR (95% CI) of 1.52 (1.35–1.72), p value of less than 0.001 and 1.69 (1.47–1.94), p value of less than 0.001, respectively. Agitation (Index) and the number of mobilization or delirium episodes showed no association with mortality, when considered in conjunction with other variables (Table S4, Supplemental Digital Content 1, http://links.lww.com/CCM/D358).

Back to Top | Article Outline

Secondary Outcomes

Cox proportional hazard regression analysis showed that the SI was a significant predictor of reduced chance of early extubation with HR (95% CI) 0.80 (0.72–0.89), p value of less than 0.001 after 48 hours (Table 2). These results were supported by mixed linear modeling of log ventilation time, variable estimate, and SE of 0.109 (0.026), p value of less than 0.001 (Table S6, Supplemental Digital Content 1, http://links.lww.com/CCM/D358). The positive association of SI in the first 48 hours and log ventilation time for patients ventilated longer than 48 hours also showed an approximately linear relationship (Fig. S2, Supplemental Digital Content 1, http://links.lww.com/CCM/D358). The Tertiles of SI showed a stepped-up increase in the median ventilation time, log rank p value of less than 0.001 (Fig. 2B).

Both Sedation and Agitation Index in the first 48 hours showed a significant predictor of increased risk of subsequent delirium HR (95% CI) of 1.25 (1.10–1.43), p value equals to 0.001 and 1.25 (1.04–1.49), p value equals to 0.02, respectively. These findings were supported by logistic regression for the prediction of any delirious event post 48 hours odds ratio (95% CI), 1.39 (1.17—1.64), p value of less than 0.001 and 1.34 (1.04–1.73), p value equals to 0.03, respectively (Table S5, Supplemental Digital Content 1, http://links.lww.com/CCM/D358). This positive association exhibited an escalating relationship in spline smoother (Fig. S3, Supplemental Digital Content 1, http://links.lww.com/CCM/D358) with a stepped-up increase in delirium in Tertiles of SI (Fig. S4, Supplemental Digital Content 1, http://links.lww.com/CCM/D358).

SI also predicted increased ICU stay and hospital length of stay in survivors, variable estimates, and SE (0.097 [0.024]; p < 0.001) and (0.094 [0.029]; p = 0.002), respectively (Tables S7 and S8, Supplemental Digital Content 1 http://links.lww.com/CCM/D358).

In the first 48 hours after mechanical ventilation, 60%, 47%, 47%, 48%, and 10% of patients received midazolam, propofol, morphine, fentanyl, and/or dexmedetomidine, respectively. There was no evidence of a difference in the relationship between SI and survival to 180-day according to sedative agents administered in the first 48 hours.

Back to Top | Article Outline

DISCUSSION

Key Findings

In this data analyses, the intensity of sedation, measured by the SI, in the first 48 hours following mechanical ventilation revealed a significant, independent escalating dose-dependent association with 180-day survival, time to extubation, and subsequent delirium. For every one point increase in sedation intensity, the predicted risk of death at 180-day increased by nearly 30% and the risk of subsequent delirium by 25%, while the time to extubation was delayed by 24 hours. On the other hand, agitation and prior delirium, before first 48 hours, tripled the risk of subsequent (after 48 hr) delirium. In contrast, other components of sedation practice did not show any independent association with 180-day survival.

Our study systematically evaluated all key variables of sedation practice. These have not generally been assessed together in other sedation studies. In contrast to our previously published reports (4), we assessed sedation intensity, using the SI as a continuous measure, over time rather than at a single time point. This has revealed a dose-dependent relationship between sedation intensity and time to death, extubation, and delirium. This biological gradient has not been demonstrated previously. We have also expanded the exposure window with analysis performed at 5 and 7 days evaluating the relationship between mobilization, delirium, and 180-day mortality.

The independent association of delirium with mortality is still debated. Some reports have suggested a significant link between delirium and mortality (12 , 13), whereas others reported a weak association with mortality (14). Our findings suggest that, after adjustment for the sedation intensity, the association between delirium and mortality may not be significant. Earlier reports suggested that shorter ventilation time and reduced delirium were associated with increased physical activity and mobilization (15). Recent reports, however, found no improvement in functional capacity with such interventions (16). Our data suggest that mobilization episodes up to 7 days following mechanical ventilation did not show any independent association with 180-day mortality.

Finally, the association of sedation intensity with 180-day survival was influenced to a small degree by admission diagnosis, and this interaction was most pronounced in septic patients. This is in concordance with reports suggesting a differential benefit of light sedation in septic patients (17).

Back to Top | Article Outline

Implications of Study Findings

Although there is no consensus on what constitutes light sedation, our study supports the premise that providing the lightest sedation level (assessed by the SI), unless contraindicated, is likely desirable (18–21) and is in concordance with recommendations by the Society of Critical Care Medicine Clinical Practice Guidelines (1). It expands, however, our current knowledge and understanding of early sedation practice and associated outcomes.

We suggest that sedation intensity, measured by the SI, enhances the utility of current validated sedation scales such as the RASS. It takes into account an important dimension, time. Our study gives an evidence-based alternative to the implicit consensus, which arbitrarily defines light sedation as RASS –2 to +1 by showing that there is, in fact, an escalating relationship between the intensity of sedation and risk of death, log ventilation time, and risk of subsequent delirium. It also suggests that to reduce the harm associated with sedation, sedation level should be equivalent to a RASS of 0 (Comfortable, Cooperative, and Calm—the triple C rule), unless contraindicated (22). Furthermore, it addresses the lack of data to inform the relationship between the continuum of early sedation depth (RASS –5 to –1) and long-term outcomes. Finally, it provides a time window where interventions may be possible, desirable, and more effective.

Our findings, compared with other related early practice variables (pain, agitation, mobilization, and delirium), imply that sedation intensity (a modifiable factor when clinically desirable) has primacy over other components of sedation practice. It also infers a need to develop objective means of continuously assessing sedation intensity (23–25).

Back to Top | Article Outline

Strengths and Limitations

This study has several strengths. It was conducted in a large cohort of hundreds of patients with thousands of assessments in 42 ICUs in four countries with diverse medical systems, using frequent and standardized assessment of pain, agitation, sedation, delirium, and mobilization by specially trained staff, and longitudinal rigorous detailed collection of data on all interventions and sedative agents given, with very low loss to follow-up and robust statistical modeling and analysis.

This study also has some limitations. Our study did not assess other important long-term outcomes such as cognitive and neuropsychologic function; thus, we make no assumptions in this regard. A limitation of our data derives from the limited frequency of RASS observations, the lack of data on episodes of change in the RASS and the likely bias to measure RASS in patients who appear more awake. A further limitation is the limited information available on the interaction between the presence of agitation, the use and dose of sedative drugs, the use and dose of antidelirium medications, and the possibility that a very low RASS may represent the effect of illness rather than sedation. In addition, delirium may have been underestimated, with once daily assessment. Furthermore, despite rigorous data collection and statistical adjustments for known confounders, important covariates may exist, which affected our findings, and were not identified in our study. However, the escalating relationship between depth of sedation and long-term outcome provides support for an intensity-related effect. Finally, this study does not represent evidence of causality but is simply hypothesis generating. Nonetheless, studies such as ours provide the necessary epidemiologic underpinnings for the justification and design of interventional studies.

Back to Top | Article Outline

CONCLUSIONS

Sedation intensity, measured by the SI, within the first 48 hours of ventilation was independently associated, in an escalating, intensity-dependent manner, with increased 180-day mortality, subsequent delirium, and delayed time to extubation. In contrast, pain, agitation, delirium, and mobilization, even up to 7 days following mechanical ventilation, exhibited no apparent relationship with 180-day mortality. These findings suggest that a sedation level targeted to calm and awake state may be an important and desirable goal of management.

Back to Top | Article Outline

REFERENCES

1. Barr J, Fraser GL, Puntillo K, et al; American College of Critical Care Medicine: Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med 2013; 41:263–306
2. Grounds M, Snelson C, Whitehouse T, et al. Intensive Care Society Review of Best Practice for Analgesia and Sedation in Critical Care. 2014London, The Intensive Care Society of the United Kingdom.
3. Shehabi Y, Bellomo R, Mehta S, et al. Intensive care sedation: The past, present and the future. Crit Care 2013; 17:322
4. Shehabi Y, Bellomo R, Reade MC, et al; Sedation Practice in Intensive Care Evaluation (SPICE) Study Investigators; ANZICS Clinical Trials Group: Early intensive care sedation predicts long-term mortality in ventilated critically ill patients. Am J Respir Crit Care Med 2012; 186:724–731
5. Shehabi Y, Chan L, Kadiman S, et al; Sedation Practice in Intensive Care Evaluation (SPICE) Study Group investigators: Sedation depth and long-term mortality in mechanically ventilated critically ill adults: A prospective longitudinal multicentre cohort study. Intensive Care Med 2013; 39:910–918
6. Balzer F, Weiß B, Kumpf O, et al. Early deep sedation is associated with decreased in-hospital and two-year follow-up survival. Crit Care 2015; 19:197
7. Tanaka LM, Azevedo LC, Park M, et al; ERICC study investigators: Early sedation and clinical outcomes of mechanically ventilated patients: A prospective multicenter cohort study. Crit Care 2014; 18:R156
8. Sessler CN, Gosnell MS, Grap MJ, et al. The Richmond Agitation-Sedation Scale: Validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med 2002; 166:1338–1344
9. Riker RR, Shehabi Y, Bokesch PM, et al; SEDCOM (Safety and Efficacy of Dexmedetomidine Compared With Midazolam) Study Group: Dexmedetomidine vs midazolam for sedation of critically ill patients: A randomized trial. JAMA 2009; 301:489–499
10. Jakob SM, Ruokonen E, Grounds RM, et al; Dexmedetomidine for Long-Term Sedation Investigators: Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: Two randomized controlled trials. JAMA 2012; 307:1151–1160
11. Gélinas C, Fillion L, Puntillo KA, et al. Validation of the critical-care pain observation tool in adult patients. Am J Crit Care 2006; 15:420–427
12. Ely EW, Shintani A, Truman B, et al. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA 2004; 291:1753–1762
13. Shehabi Y, Riker RR, Bokesch PM, et al; SEDCOM (Safety and Efficacy of Dexmedetomidine Compared With Midazolam) Study Group: Delirium duration and mortality in lightly sedated, mechanically ventilated intensive care patients. Crit Care Med 2010; 38:2311–2318
14. Klein Klouwenberg PM, Zaal IJ, Spitoni C, et al. The attributable mortality of delirium in critically ill patients: Prospective cohort study. BMJ 2014; 349:g6652
15. Schweickert WD, Pohlman MC, Pohlman AS, et al. Early physical and occupational therapy in mechanically ventilated, critically ill patients: A randomised controlled trial. Lancet 2009; 373:1874–1882
16. Walsh TS, Salisbury LG, Merriweather JL, et al; RECOVER Investigators: Increased hospital-based physical rehabilitation and information provision after intensive care unit discharge: The RECOVER randomized clinical trial. JAMA Intern Med 2015; 175:901–910
17. Pandharipande PP, Sanders RD, Girard TD, et al; MENDS investigators: Effect of dexmedetomidine versus lorazepam on outcome in patients with sepsis: An a priori-designed analysis of the MENDS randomized controlled trial. Crit Care 2010; 14:R38
18. Treggiari MM, Romand JA, Yanez ND, et al. Randomized trial of light versus deep sedation on mental health after critical illness. Crit Care Med 2009; 37:2527–2534
19. Kress JP, Pohlman AS, O’Connor MF, et al. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med 2000; 342:1471–1477
20. Girard TD, Kress JP, Fuchs BD, et al. 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. Lancet 2008; 371:126–134
21. Strøm T, Martinussen T, Toft P. A protocol of no sedation for critically ill patients receiving mechanical ventilation: A randomised trial. Lancet 2010; 375:475–480
22. Vincent JL, Shehabi Y, Walsh TS, et al. Comfort and patient-centred care without excessive sedation: The eCASH concept. Intensive Care Med 2016; 42:962–971
23. Walsh TS, Kydonaki K, Lee RJ, et al; Development and Evaluation of Strategies to Improve Sedation practice in inTensive care Study Investigators: Development of process control methodology for tracking the quality and safety of pain, agitation, and sedation management in critical care units. Crit Care Med 2016; 44:564–574
24. Walsh TS, Kydonaki K, Antonelli J, et al; Development and Evaluation of Strategies to Improve Sedation Practice in Intensive Care (DESIST) study investigators: Staff education, regular sedation and analgesia quality feedback, and a sedation monitoring technology for improving sedation and analgesia quality for critically ill, mechanically ventilated patients: A cluster randomised trial. Lancet Respir Med 2016; 4:807–817
25. Walsh TS, Everingham K, Frame F, et al. An evaluation of the validity and potential utility of facial electromyelogram Responsiveness Index for sedation monitoring in critically ill patients. J Crit Care 2014; 29:886.e1–886.e7
Back to Top | Article Outline

APPENDIX 1. SEDATION PRACTICE IN INTENSIVE CARE EVALUATION (SPICE) STUDY INVESTIGATORS

Australia: Albury Base Hospital, Albury: E. Ibrom, C. Maher, C. Mashonganyika, H. McKee; The Alfred Hospital, Melbourne: V. Bennett, D. J. Cooper, S. Vallance; Austin Health, Melbourne: R. Bellomo, G. Eastwood, L. Peck, M. Reade, H. Young; Box Hill Hospital, Melbourne: S. Eliott, I. Mercer, J. Sidhu, A. Whitfield; Calvary Hospital, Canberra: G. Ding, P. Hatfield, K. Smith; Central Gippsland Health Service, Sale: T. Coles, J. Dennett, T. Summers; Concord Hospital, Sydney: R. Anderson, E. Jones, D. Milliss, H. Wong; Frankston Hospital, Melbourne: J. Botha, S. Allsop; Lyell MeEwin Hospital, Adelaide: M. Kanhere, J. Wood, C. Hogan, J. Tai, T. Williams; Nambour Hospital, Nambour: A. Buckley, P. Garrett, S. McDonald; Nepean Hospital, Sydney: C. Cuzner, I. Seppelt, L. Weisbrodt; Prince of Wales Hospital, Sydney: F. Bass, P. Edhouse, M. Sana, Y. Shehabi; Royal Perth Hospital, Perth: J. Chamberlain, S. Webb; Sir Charles Gairdner Hospital, Perth: A. Bicknell, B. Roberts; St George Hospital, Sydney: E. Casey, A. Cheng, D. Inskip, J. Myburgh; St. Vincent’s Hospital, Melbourne: J. Holmes, J. Santamaria, R. Smith; St. Vincent’s Hospital, Sydney: P. Nair, C. Reynolds; and Wollongong Hospital, Wollongong: B. Johnson, M. Sterba. Malaysia: University of Malaya: Dr. K. K. Wong, Dr. Suresh Venugopal, Dr. Vineya Rai, Dr. Mohd Shahnaz, Vimala Ramoo (Nurse Lecturer); National Heart Institute: Dr. Smitha Jose, Dr. Ozlem Ozturk, S. N. Zuraida Ramlee, Bong Siu Foon (Staff Nurse), Rohana Amran (Staff Nurse); Hospital Melaka: Dr. R. K. Anusha Narula, Dr. Erin Shazrin Md Ramly, Dr. Khalidah Abdul Hapiz, Dr. Lim I-Liang, Dr. Mohamad Hafiz Che Morad; Hospital Raja Perempuan Zainab II: Dr. Mohd Nazri Ali, Dr. H. Noor Raihan, Sister I. Azizum, Y. Suzana (Staff Nurse), H. Haryati (Staff Nurse); Kuala Lumpur General Hospital: S. Salmi Zawati (Staff Nurse), J. Nur Ismeev (Staff Nurse); Hospital Queen Elizebeth: Dr. Mohd Ashraf Zulkarnain; Hospital University Sains Malaysia: Associate Professor Dr. Mahamarowi Omar, Dr. Siti Aisah Omar, Sister Rokian Ismail, Norhamilah Hassan (Staff Nurse), Zanariah Zakaria (Staff Nurse); Sarawak General Hospital: Dr. Sanah Mohtar, Dr. Marina Ahmad, Winnie Suai (Staff Nurse), Wong Ai Li (Staff Nurse), Jong Siaw Lan (Staff Nurse); Hospital Sultanah Bahiyah: Dr. S. Siti Rohayah. Dr. Fitriah Mahadir, Teoh Shook Lian (Staff Nurse), Maryam Md Zain (Staff Nurse), Noorasmah Ahmad (Staff Nurse); Hospital Sultanah Aminah: Dr. K. Mahazir, A’ishah Abu Bakar (Staff Nurse); and Penang General Hospital: Dr. Ho Wing Nan, Sister Tan Ai Ping, Sister Chin Lai Ngan, Dr. Lim Chiew Har, Dato Dr. Jahizah Hassan. New Zealand: Auckland City Hospital CVICU, Auckland, NZ: J. Brown, E. Gilders, R. Parke; Auckland City Hospital DCCM, Auckland, NZ: C. McArthur, L. Newby, C. Simmonds; Christchurch Hospital, Christchurch, NZ: S. Henderson, J. Mehrtens; Middlemore Hospital, Auckland, NZ: Tauranga Hospital, Tauranga, NZ: T. Browne, D. Cubis, J. Goodson, S. Nelson; and Wellington Hospital, Wellington, NZ: D. Mackle, S. Pecher. Singapore: National University Hospital, Singapore: L. Ti, D. Lim, A. Mukhopadhyay; Tan Tock Seng Hospital, Singapore: Y. Wong, B. Ho; Khoo Teck Puat Hospital, Singapore: N. Chia; and Singapore General Hospital, Singapore: N. Yi, G. Kalyanasundaram.

Keywords:

critically ill; delirium; mechanical ventilation; mobilization; mortality; sedation intensity

Supplemental Digital Content

Back to Top | Article Outline
Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.