Sedative and Analgesic Medications: Risk Factors for Delirium and Sleep Disturbances in the Critically Ill

Postoperative delirium (POD) has become a critical challenge with severe consequences and increased incidences as the global population ages. However, the underlying mechanism is yet unknown. Our study aimed to explore the changes in metabolites in three specific brain regions and saliva of older mice with postoperative delirium behavior and to identify potential non-invasive biomarkers.

Eighteen-month-old male C57/BL6 mice were randomly assigned to the anesthesia/surgery or control group. Behavioral tests were conducted 24 h before surgery and 6, 9, and 24 h after surgery. Complement C3 (C3) and S100 calcium-binding protein B protein (S100beta) levels were measured in the hippocampus, and a metabolomics analysis was performed on saliva, hippocampus, cortex, and amygdala samples.

In total, 43, 33, 38, and 14 differential metabolites were detected in the saliva, hippocampus, cortex, and amygdala, respectively. “Pyruvate” “alpha-linolenic acid” and “2-oleoyl-1-palmitoy-snglycero-3-phosphocholine” are enriched in one common pathway and may be potential non-invasive biomarkers for POD. Common changes were observed in the three brain regions, with the upregulation of 1-methylhistidine and downregulation of D-glutamine.

Dysfunctions in energy metabolism, oxidative stress, and neurotransmitter dysregulation are implicated in the development of POD. The identification of changes in the level of salivary metabolite biomarkers could aid in the development of noninvasive diagnostic methods for POD.

Neurologic morbidity is highly prevalent in pediatric critical illness, and the use of benzodiazepines and/or opioids is a risk factor for delirium and post-discharge sequelae. However, little is known about how multidrug sedation with these medications interacts with inflammation in the developing brain, a frequent condition during childhood critical illness that has not been extensively studied. In weanling rats, mild-moderate inflammation was induced with lipopolysaccharide (LPS) on postnatal day (P)18 and combined with 3 days repeated opioid and benzodiazepine sedation using morphine and midazolam (MorMdz) between P19–21. Delirium-like behaviors including abnormal response to whisker stimulation, wet dog shakes, and delay in finding buried food were induced in male and female rat pups treated with LPS, MorMdz, or LPS/MorMdz (n ≥ 17/group) and were compared using a z-score composite. Composite behavior scores were significantly increased in LPS, MorMdz, and LPS/MorMdz groups compared to saline control (F_3,78 = 38.1, p < 0.0001). Additionally, expression of glial-associated neuroinflammatory markers ionized calcium-binding adaptor molecule 1 (Iba1) and glial fibrillary acidic protein (GFAP) in western blots of P22 brain homogenate were significantly higher after LPS than after LPS/MorMdz (Iba1, p < 0.0001; GFAP, p < 0.001). Likewise, proinflammatory cytokines were increased in brains of LPS-treated pups versus Saline (p = 0.002), but not LPS/MorMdz-treated pups (p = 0.16). These results are of potential interest during pediatric critical illness, as inflammation is ubiquitous and the effects of multidrug sedation on homeostatic neuroimmune responses need to be considered along with neurodevelopmental effects.

To assess the efficacy of melatonin and melatonergic agonist for the treatment of delirium in hospitalized patients.

Embase, MEDLINE, PsycINFO, PubMed, CENTRAL, Cochrane Database of Systematic Reviews, TRIP Medical Database, ClinicalTrials.gov and Google were searched from inception to October 2022. Randomized controlled trials (RCT) and observational studies with any type of comparator evaluating melatonin or melatonergic agonist (ramelteon) enrolling any populations (ICU, surgery, geriatric) were included. Two reviewers independently selected and extracted data using the Cochrane risk of bias tools (RoB2 and ROBINSI).

Out of the 650 screened publications, three RCTs and six observational studies were included (n = 1211). All three RCTs compared melatonin to placebo, as the majority of observational studies compared melatonin or ramelteon to antipsychotics. Two RCTs reported the duration of delirium and a meta-analysis provided a statistical difference between melatonin and placebo (−1.72 days, 95% CI –2.66 to −0.77, p = 0.0004). Five observational studies reported the duration of delirium but only one reported a statistical reduction in the duration of delirium.

Although melatonin and ramelteon may be effective treatments for delirium, particularly to shorten the duration of delirium and to limit the use of rescue medication, current data is limited in number and in its quality. Clinicians should wait until higher quality data from ongoing RCTs are available before prescribing melatonin to delirious patients.

Sleep paralysis is a common phenomenon which causes and consequences are seldomly studied. The aim of this study was to investigate the incidence and prevalence of sleep paralysis (SP) in the American adult population and its evolution on a 3-year period.

This longitudinal study was conducted between 2002 and 2015 and included a representative sample of the US general population. A total of 12,218 subjects were initially interviewed (W1) and 10,931 were re-interviewed three years later (W2). The subjects participated in telephone interviews using the Sleep-EVAL expert system. Each interview lasted for about 1 h. SP episodes were assessed according to their frequency and duration.

At W1, 9.7% (95%CI: 9.1%–10.3%) reported having ≥1 episode of SP in the previous year. At W2, 15.1% (95%CI: 14.4%–15.8%) reported SP. A total of 29.9% of subjects with SP at W1 still reported episodes at W2. The 1-year incidence was 2.7% (95%CI: 2.4–3.0%). After adjusting for age and sex, prevalent SP (i.e., present at W2) was predicted by age and race and the following factors present at W1: major depressive disorder, pain, hypersomnolence, cataplexy, hypnagogic and hypnopompic hallucinations, posttraumatic stress disorder, a reduction in sleep duration of ≥60 min, and the use of analgesic/antipyretic medication. Incident SP (i.e. new cases at W2) had similar predictive factors.

Episodes of SP are frequent in the general population. Its persistence is predicted by several factors associated with narcolepsy like hypersomnolence and cataplexy but also by other factors like posttraumatic stress disorder or pain.