Introduction
Sedation is an important component of care for patients under mechanical ventilation (MV) in the ICU. Significant distress is related to MV itself or to routine procedural interventions [
1] and minimizing pain, anxiety and distress is a major recommendation in recent guidelines [
2]. Pain and anxiety control is usually obtained with analgesics and sedatives that ensure comfort, improve synchrony with the ventilator and decrease work of breathing [
3]. Some studies, however, have shown that oversedation is associated with poor outcomes, including delirium, prolonged MV, ventilator-associated pneumonia, long ICU and hospital length of stay [
3‐
6], posttraumatic stress disorder [
7] and cognitive impairment [
8,
9] as well as increased costs [
10‐
12]. Nevertheless, the issue of early sedation has seldom been evaluated, especially in randomized controlled studies.
Despite the current recommendations [
2], there is still a significant gap between evidence from recent trials and implementation in clinical practice [
2,
6,
13,
14]. Moreover, to date no large randomized controlled trials of sedation strategies used mortality as the primary outcome. In addition, clinical trials of sedation have until now enrolled patients mostly after 24 to 48 hours following initiation of MV, resulting in inadequate assessment of early sedation practice and its association with clinically relevant outcomes [
15‐
17].
The aim of this study is thus to describe the association of early sedation strategies (sedation depth and sedative choice) with clinical outcomes of mechanically ventilated adult ICU patients, with hospital mortality as the primary outcome.
Discussion
In the present multicenter cohort study we evaluated the association of early sedation strategies with outcomes of adult mechanically ventilated patients in the ICU. Deep sedation in the first 48 hours of MV is a common characteristic, observed in 35.1% of patients. Deep sedation was associated with increased disease severity, longer duration of ventilatory support and higher need for tracheostomy. In a multivariate analysis, deep sedation was an independent factor associated with increased hospital mortality (odds ratio = 2.36).
The more frequently used sedative regimens in our study were the association of midazolam and fentanyl or of propofol and fentanyl. When compared by sedation depth, the administration of fentanyl or dexmedetomidine as single drugs was more frequent in lightly sedated patients (15.3% vs. 7.1% for fentanyl,
P = 0.033; 8.6% vs. 0.9% for dexmedetomidine,
P = 0.005). These findings may be attributed to a rapid onset and offset of action of these drugs and their easiness to titrate, while benzodiazepines are more likely to accumulate, especially during continuous infusion and when associated with other drugs [
26,
27]. Recent studies demonstrate that sedation with benzodiazepines aiming at the same target is usually associated with a higher rate of sedation depth beyond the target as compared with dexmedetomidine [
28].
Although important studies were published recently, a systematic review published in 2010 showed that clinical trials on sedation are commonly reported as low quality, mainly due to their design (for example, before and after studies), heterogeneous protocols and the relatively small number of patients in a single center or few centers [
29]. These factors generate limited evidence to guide sedation drug choice and administration strategies in mechanically ventilated patients. Moreover, most studies – including recent randomized clinical trials – have enrolled patients 24 to 48 hours after the initiation of MV, making the clinical relevance of sedation depth in the early period more difficult to understand. A recent multicenter prospective cohort study by Shehabi and colleagues enrolled 251 patients, aiming to characterize the patterns of early sedation practice in 25 Australia and New Zealand (ANZ) ICUs and to assess its relationship with relevant clinical outcomes. After adjusting for potential confounding, early deep sedation was a predictor of time to extubation and mortality [
30]. These results were corroborated by a cohort study in 11 Malaysian hospitals including medical/surgical patients (
n = 259) who were sedated and ventilated ≥24 hours [
31]. Likewise, in our study we could assess sedation strategies in the first 48 hours of MV and its relevant clinical outcomes in a large number of patients (
n = 322), and demonstrated that early deep sedation was an independent predictor of hospital mortality.
Unlike the other variables that were also found to be independently associated with mortality in our study, such as ARDS severity, comorbidities and disease severity, sedation depth is a potentially modifiable risk factor for mortality. Implementing sedation protocols to achieve light sedation has been proven feasible and reproducible [
32,
33]. This evidence is important because deep sedation still seems to be current practice in many ICUs worldwide [
5,
13] and is present in 35% of the patients enrolled in the present study. Accordingly, Payen and colleagues observed in their survey a large proportion of patients in a deep state of sedation, and in addition no major changes in sedation depth or sedative dosages occurs during the first week of the ICU stay [
34].
Finally, our findings provide validation of the concept that early sedation has a major impact on outcomes. Demonstrating this in a middle-income country in South America is an important step to provide generalizability of previous findings because the main previously published results on this issue are from ANZ ICUs. Several ANZ trials are well known for frequently presenting different results compared with similar interventions in other parts of the world, as demonstrated by studies in the last decade in the critical care field [
35,
36] and even in the sedation area [
37]. This discrepancy is attributed to substantial differences due to the high standards in process of care and staffing patterns, and is consequently translated into lower mortality in ANZ ICUs [
38,
39].
The present study has some limitations that must be considered. First, the sedation level was not assessed using a specific sedation scale. Nonetheless, although originally created to assess the level of consciousness after head injury, it is known that GCS (the chosen scale) <9 denotes a comatose state even in nontraumatic settings, such as cerebral depression by pharmacological cause [
40,
41]. Moreover, the GCS shows excellent correlation and discrimination with the RASS (
r = 0.91,
P < 0.001), as described by Ely and colleagues from 1,360 paired observations among 275 adult patients in medical and coronary ICUs [
25]. This strong correlation between the RASS and the GCS was also shown in other sedation scale validation studies [
42,
43], which allows its applicability as a surrogate for sedation depth in the present study.
Another limitation is the potential influence of previous neurological status on GCS values. Data regarding GCS on day 1 were collected in patients who were already sedated and under MV. A reported low GCS could therefore be influenced by the baseline neurological status and not only by sedation strategies, because it may also reflect acute neurological conditions associated with the current illness presented by the critically ill, such as encephalopathy. However, this is not an exclusive limitation of the GCS because this may also occur with the more specific sedation assessment scales such as the RASS or Sedation-Agitation Scale (SAS). Moreover, it is possible that certain patients may have required larger sedative doses on day 2 of MV for other reasons (ICU procedures, for instance) and we did not collect these data. In order to minimize the impact of other conditions in GCS values, we excluded patients with primary or known acute neurological disorders and included only patients under sedation in the present study. Considering the potential confounders mentioned above, the strong association between deep sedation and mortality must be analyzed regarding our interpretation of GCS values mainly as a surrogate of sedation depth.
Finally, we have not evaluated the presence of delirium. In mechanically ventilated patients, delirium is an independent predictor of hospital and 6-month mortality [
6,
44]. These outcomes are shown even in light sedated patients, where a dose–effect response was described [
45]. Despite this clinical relevance, the incidence of delirium could not be evaluated in our study, since it was not the aim of the primary analysis. Finally, participant ICUs reported the existence of a sedation protocol, but the actual adherence for local recommendations was not assessed in the present study as it was beyond its initial scope.
Competing interests
This study was performed with institutional funds. JIFS received honoraria and unrestricted research grants from Hospira, Inc. São Paulo, Brazil, but this did not interfere with the design, analysis or the elaboration of the manuscript and therefore with adherence to the ethical requirements of the journal. The remaining authors declare that they have no competing interests.
Authors’ contributions
LMST participated in study conception, data acquisition, data analysis and interpretation, and drafting of the manuscript. LCPA participated in study conception, data acquisition, data analysis and interpretation, and drafting of the manuscript. MP participated in study conception, data analysis and revising the manuscript for important intellectual content. GS participated in study conception, data acquisition, data analysis and drafting of the manuscript. APNJr participated in data acquisition, drafting of the manuscript and revising the manuscript for important intellectual content. AR-N participated in data acquisition and revising the manuscript for important intellectual content. LT participated in data acquisition and revising the manuscript for important intellectual content. VCdS-D participated in data acquisition and revising the manuscript for important intellectual content. AT participated in data acquisition and revising the manuscript for important intellectual content. TL participated in data acquisition and revising the manuscript for important intellectual content. CP participated in data acquisition and revising the manuscript for important intellectual content. FBC participated in data acquisition and revising the manuscript for important intellectual content. MdOM participated in data acquisition and revising the manuscript for important intellectual content. FPG participated in data acquisition and revising the manuscript for important intellectual content. FRM participated in data acquisition and revising the manuscript for important intellectual content. FD-P participated in data acquisition and revising the manuscript for important intellectual content. AGRdC participated in data acquisition and revising the manuscript for important intellectual content. RBdS participated in data acquisition and revising the manuscript for important intellectual content. PFGMMT participated in data acquisition and revising the manuscript for important intellectual content. MS participated in study conception, data analysis and interpretation, and drafting of the manuscript. JIFS participated in study conception, data analysis and interpretation, and drafting of the manuscript. All authors approved the final copy of the manuscript.