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