Background
Sedation and analgesia are essential components in the care of mechanically ventilated patients in the intensive care unit (ICU) to provide comfort, improve patient-ventilator synchrony, and reduce anxiety and agitation [
1]. However, deep sedation has been associated with negative patient-centered outcomes including delirium [
2,
3], a common complication in the ICU, with a prevalence as high as 82% [
4]. This preventable complication is an independent predictor of mortality [
4‐
6] and is also associated with long-term cognitive impairment and disability [
7‐
9]. Optimizing sedation practices and delirium screening with the use of protocols is associated with improved patient-centered outcomes such as a lower incidence of delirium [
2,
10], fewer days on mechanical ventilation [
11,
12], and an overall reduction in mortality [
12,
13]. Additionally, standardized management of sedation reduces the use of sedatives without negatively affecting patient safety or increasing psychological stress [
14].
Despite these recognized benefits, sedation practices remain variable, with a tendency towards over-sedation and a lack of routine delirium assessment [
1,
15]. Less is known about sedation practices and delirium management for the critically ill in resource-limited settings, where mortality is higher in the USA or Europe [
16]. We hypothesize that the higher mortality and longer length of stay in ICUs in resource-limited settings could be partly explained by suboptimal sedation and delirium management. In this study, we explore the association between sedation status, use of sedation and antipsychotics medications, and patient centered-outcomes in a cohort of critically ill, mechanically ventilated patients in five ICUs in Lima, Peru.
Discussion
We found that deep sedation, agitation, and benzodiazepines were independently associated with worse clinical outcomes. Specifically, a greater percentage of days spent in deep sedation (i.e., 75th vs 25th percentile of days in deep sedation) was associated with a fivefold greater odds of mortality and a 4- to 7-point reduction in ventilator-free, ICU-free, and hospital-free days. Agitation status had a 40-fold higher mortality. The interquartile cumulative difference in benzodiazepine usage was associated with a 41% higher odds of 90-day mortality. Additionally, we reported that the usage of antipsychotics was associated with lower 90-day mortality. We identified that most of our critically ill participants undergoing mechanical ventilation were deeply sedated throughout their ICU stay. The most common used sedatives were opioids and benzodiazepines.
Our findings confirm the known relationship between sedation depth and use of benzodiazepines with adverse outcomes. Our results regarding the association between deep sedation and mortality as well as deep sedation and decrease in the secondary outcomes are consistent with previous similar studies [
25,
26]. However, in our cohort of patients, significant variation of sedation depth as reported by Shehabi et al. [
25] is not present. Unfortunately, most of our enrolled participants remained deeply sedated past the first 48 h after initiation of mechanical ventilation.
In our study, we identified an independent relationship between benzodiazepines and mortality. Previous studies support the current recommendations of non-benzodiazepine agents [
27,
28]. In a recent meta-analysis by Fraser et al. that included six trials enrolling 1235 critically ill participants, the use of non-benzodiazepine sedation in medical and surgical adult ICU patients was not associated with a statistically significant increase in mortality but was associated with 1.65-day shorter length of ICU stay and 1.9-day shorter duration of mechanical ventilation compared to patients receiving benzodiazepines for sedation [
29].
None of the five ICUs participating in this study used protocols for sedation management, nor did they use tools to screen or manage delirium [
17]. This is not surprising since data from previous international surveys reported implementation rates between 20% and 80% [
1], including a study of 912 ICU practitioners in high-income countries that revealed that only 16% used a valid delirium assessment tool [
30]. We show that physicians in Peruvian ICUs mainly use benzodiazepines and opioids, and the use of dexmedetomidine is still limited. One of the reasons for the low usage of dexmedetomidine could be its high price; however, when considering the potential benefits, it is possible that it may actually be more cost-effective than using benzodiazepines [
31].
Notably, our study showed that the use of haloperidol was associated with a lower mortality in ICU patients. Even though we did not assess delirium directly in our patients, we used haloperidol as a surrogate for the treatment of ICU delirium. Previous evidence shows that the use of antipsychotics could reduce the incidence of delirium [
32]. The effect of delirium management with antipsychotic medications on mortality in critically ill patients is unknown, and adequately powered randomized control trials are needed. However, a recent randomized controlled trial that used haloperidol or ziprasidone, as compared with placebo, in patients with acute respiratory failure or shock and hypoactive or hyperactive delirium in the ICU did not find a reduction in secondary outcomes such as 30-day or 90-day mortality [
33].
There are important limitations in this study. First, we did not evaluate for delirium. However, evaluation of delirium was not an aim of the primary study and participating ICUs did not use delirium screening scales. Nonetheless, assessment of delirium using the CAM-ICU [
34] or another validated survey would have provided a better understanding of the magnitude of the problem, given that delirium is a well-recognized factor that affects sedation practices [
35]. Second, the assessment of sedation depth was conducted with non-standard instruments like the Glasgow Coma Scale [
20]. Nevertheless, the Glasgow Coma Scale has a strong correlation with RASS Sedation Scale [
22]. Still, given the design of the Glasgow Coma Scale, agitation status could have been underestimated. Another limitation is that we did not take into account the primary pathology when evaluating sedation practices. Primary strengths of this study are that it is a large prospective multicenter assessment of routine practices in a broad range of critically ill patients undergoing mechanical ventilation. Additionally, it provides detailed data about sedation practices and their impact on patient outcomes throughout the ICU stay in a middle-income country, which is very important for generalizing previous findings from high-income settings. Another important strength resides in the high quality of our data, assured by a tiered approached quality control of the report forms, double-data entry, and a centrally coordinated database.
Conclusions
The results of our study indicate that despite strong evidence that correlates sedation depth with worse clinical outcomes, most ICU patients were deeply sedated during their ICU stay. This high level of sedation could potentially account for the high mortality observed in our patient population and warrants timely sustainable implementation strategies that apply to low- and middle-income countries, such as standardized protocols. However, future studies should also evaluate sedation depth and mortality adjusted for newer severity scoring systems in the ICU (e.g., APACHE IV). This way, the adverse outcomes related to these preventable measures can be avoided.