Pharmacological and nonpharmacological management of delirium in critically ill patients

Abstract

Delirium is a common yet under-diagnosed syndrome of acute brain dysfunction, which is characterized by inattention, fluctuating mental status, altered level of consciousness, or disorganized thinking. Although our recognition of risk factors for delirium has progressed, our understanding of the underlying pathophysiologic mechanisms remains limited. Improvements in monitoring and assessment for delirium (particularly in the intensive care setting) have resulted in validated and reliable tools such as arousal scales and bedside delirium monitoring instruments. Once delirium is recognized and the modifiable risk factors are addressed, the next step in management (if delirium persists) is often pharmacological intervention. The sedatives, analgesics, and hypnotics most often used in the intensive care unit (ICU) to achieve patient comfort are all too frequently deliriogenic, resulting in a longer duration of ICU and hospital stay, and increased costs. Therefore, identification of safe and efficacious agents to reduce the incidence, duration, and severity of ICU delirium is a hot topic in critical care. Recognizing that there are no medications approved by the Food and Drug Administration (FDA) for the prevention or treatment of delirium, we chose anti-psychotics and alpha-2 agonists as the general pharmacological focus of this article because both were subjects of relatively recent data and ongoing clinical trials. Emerging pharmacological strategies for addressing delirium must be combined with nonpharmacological approaches (such as daily spontaneous awakening trials and spontaneous breathing trials) and early mobility (combined with the increasingly popular approach called: Awakening and Breathing Coordination, Delirium Monitoring, Early Mobility, and Exercise [ABCDE] of critical care) to develop evidence-based approaches that will ensure safer and faster recovery of the sickest patients in our healthcare system.

Fig. 1

(a) A priori subgroup analysis of the Maximizing Efficacy of Targeted Sedation and Reducing Neurological Dysfunction (MENDS) randomized controlled trial. Compared to sedation with lorazepam, sedation with dexmedetomidine resulted in a markedly reduced daily risk of delirium (p = 0.02). As noted in this article, this relationship was even more pronounced in patients with severe sepsis. Note that both groups start with 60% prevalence of delirium in keeping with most cohorts of mechanically ventilated patients, and then there is a large difference in delirium prevalence throughout the remainder of the study period. Adapted from Pandharipande, et al. [132]. (b) In the Safety and Efficacy of Dexmedetomidine Compared with Midazolam (SEDCOM) trial comparing dexmedetomidine to midazolam for sedation of mechanically ventilated patients, the prevalence of delirium in dexmedetomidine-treated patients was significantly less than midazolam-treated patients (54% vs 76.6%; p < 0.001). As in (a), both groups started with 60% prevalence of delirium and then showed a large difference in delirium prevalence throughout next week. These (a) and (b) pose the unanswered question as to whether or not it is the avoidance of a gamma-amino butyric acid (GABA)-agonist or the receipt of an alpha-2 agonist that resulted in such marked delirium reduction. Adapted from Riker, et al. [55]

Fig. 2

(a) Two investigations formed the basis for the Awakening and Breathing Controlled (ABC) trial. The first step in modern “weaning” programs is step A: spontaneous awakening trials (SATs), a daily interruption of sedatives and narcotics, which in this investigation reduced time on mechanical ventilation by 2 days. Adapted from Kress JP, et al. [151]. (b) The second step in modern day “weaning” protocols is step B: spontaneous breathing trials (SBTs), a daily interruption of the provision of ventilator support, such as turning the settings to continuous positive airway pressure (CPAP), was shown in this investigation to reduce time on mechanical ventilation by 2 days. Adapted from Ely EW, et al. [153]

Fig. 3

(a) The Awakening and Breathing Controlled (ABC) trial reduced intensive care unit stay (not shown) and hospital length of stay for mechanically ventilated patients by 4 days when daily spontaneous awakening trials (SATs) were paired with daily spontaneous breathing trials (SBTs) compared to the control group with sedation per usual care plus daily SBT. Adapted from Girard TD, et al. [54]. (b) The ABC trial was the first randomized controlled trial of any “weaning” component of critical care (i.e., the “back end of critical care”) to demonstrate that pairing spontaneous awakening trials (SATs) with spontaneous breathing trials (SBTs) increased survival, and the number needed to treat to save 1 life was 7. Adapted from Girard TD, et al. [54]

Fig. 4

Analgesia/sedation protocol for mechanically ventilated patients. This is an example of an evidence-based protocol that combines pharmacological strategies with spontaneous awakening and breathing trials, and also leads to a delirium protocol (not shown). Adapted from: http://www.mc.vanderbilt.edu/icudelirium/docs/Sedation_protocol.pdf

Fig. 5

Delirium and long-term cognitive outcomes. These data show that delirium duration was an independent predictor of neuropsychological function at 12 months, such that for every additional day of delirium up to approximately 12 days, the cognitive function of this cohort was worse when measured 1 year after ICU care (p = 0.005). Adapted from Girard TD, et al. [9]