Using three large databases, MIMIC III v1.4, MIMIC-IV v0.4 and eICU Collaborative Research, we performed a multicenter, observational cohort study to assess outcomes in patients at risk for delirium who were treated with midazolam infusions within 24 hours before delirium diagnoses were defined. We observed that delirium was diagnosed in 28.28% of the patients, and patients who used midazolam within 24 hours before diagnosis were more likely to develop delirium. Moreover, our data show that midazolam was associated with multiple detrimental outcomes including an increased risk of mortality, longer ICU stays and lower likelihood of being discharged to home. However, there was no significant association between treatment with midazolam and length of hospitalization.
Recently, published meta-analyses have demonstrated that midazolam was associated with a significantly higher rate of delirium [17, 18]. These studies were limited by small sample sizes and limited long-term observations. Another propensity score-matched cohort study showed that midazolam-dominant sedation strategies were associated with increased delirium risk, mortality, ICU length of stay and hospital days ; unfortunately, they did not test the isolated effects of midazolam and eliminate the influence of midazolam metabolism and clearance, while our study did. Additionally, a single-center analysis showed that benzodiazepine administration in an awake patient without delirium was associated with an increased risk of delirium the next day . However, a multicenter systematic comparison of the effectiveness and safety of midazolam within 24 hours prior to delirium assessment in ICU patients has been lacking.
There are multiple mechanisms by which midazolam may increase delirium. Midazolam activates γ-aminobutyric acid A (GABAA) neuronal receptors in the brain, and their activation can alter the levels of numerous neurotransmitters, such as dopamine, serotonin, acetylcholine, norepinephrine, and glutamate, which are believed to be deliriogenic [21–23]. Midazolam could indeed be involved in delirium pathogenesis through overstimulation of the cortical GABA system, thereby reducing corticostriatal glutamatergic tone and ultimately hampering the filtering action of the thalamus, leading to confusion or psychosis . In addition to altering neurotransmitter concentrations, midazolam may generate more central nervous system inhibitory effects at higher doses  and impair the quality of sleep via slow-wave sleep suppression, thus, possibly contributing to delirium [23, 26]. Moreover, a recent animal study demonstrated that midazolam or inflammation, which downregulate brain PER2 levels, led to significant hippocampus-dependent cognitive deficits, as observed in some types of delirium , The hippocampus appears to play a critical role in the pathogenesis of delirium in humans .Furthermore, midazolam alters sleep patterns and increases the risk of circadian disruption and delirium in humans [29, 30].
Delirium may increase mortality, which is not directly related to midazolam administration. Midazolam use was found to be a risk factor for delirium after liver transplantation in a systematic review and meta-analysis, which also showed that delirium was a mortality risk factor according to the pooled results of ICU mortality . Similarly, a multicenter, retrospective, cohort study by Lonardo et al demonstrated higher mortality in patients managed with benzodiazepines compared with those administered propofol. They postulated that midazolam’s mortality effect might be due to increased rates of delirium , and some evidence supports that delirium is associated with substantial morbidity both during and after ICU admission [32–34]. Each additional day of delirium increases the hazard of mortality by 10% and increases the likelihood of a poor functional status at 3 and 6 months [35–38].
Our study has three strengths. First, this retrospective cohort study included a relatively large population and accurately measured clinical variables in an actual clinical setting in a large number of ICUs. Acknowledging the possibility of confounding, we used propensity score matched analysis to balance measured pretreatment variables that may influence the effect and impact the outcomes. Second, it is important to use time-dependent multivariable analysis methods given that disease severity, midazolam administration, and delirium occurrence frequently oscillate over the course of the ICU stay. We ensured that medical treatment was provided within 24 hours before the delirium assessment to limit the influence of other confounding factors. Third, this study used data from multiple ICU databases across a range of hospital and ICU settings, which made our results accurately reflect the outcomes seen in an actual practice environment.
Several limitations of this study warrant discussion. First, this is an observational study, and thus, causal associations cannot be determined. Second, there were some missing data for multiple confounding variables, and some variables, such as drug doses, target sedation levels, treatment durations or daily data on sedation levels, could not be effectively merged or compared. Bias may still exist despite the use of propensity score matching and regression modeling to control for a variety of patient and hospital confounders. Third, we could not exclude, measure, or control for the use of intermittent midazolam dosing given on an as-needed basis. We could exclude only those patients who were administered other sedative drugs, such as opioid drugs or propofol, to ensure that they received the same medication. Fourth, our study was a retrospective cohort study based on electronic healthcare records, and the data were generated during routine clinical visits. Since the MIMIC-III data ranged from 2001 to 2015, eICU Collaborative Research data ranged from 2014-2015 and MIMIC- IV data ranged from 2018-2019, our results were adjusted for the admission period.