Steroid-Induced Sleep Disturbance and Delirium: A Focused Review for Critically Ill Patients
Objective: Insomnia and delirium have gained much attention since the publication of recent guidelines for the management in critically ill adults. Neurologic effects such as sleep disturbance, psychosis, and delirium are commonly cited adverse effects (AEs) of corticosteroids. Steroid use is considered a modifiable risk factor in intensive care unit patients; however, reported mechanisms are often lacking. This focused review will specifically evaluate the effects of steroids on sleep deprivation, psychosis, delirium, and what is known about these effects in a critically ill population.
Observations: The medical literature proposes 3 pathways primarily responsible for neurocognitive AEs of steroids: behavior changes through modification of the hypothalamic-pituitary-adrenal axis, changes in natural sleep-wake cycles, and hyperarousal caused by modification in neuroinhibitory pathways. Initial search fields produced 285 articles. Case reports, reviews, letters, and articles pertaining to primary care or palliative populations were excluded, leaving 8 relevant articles for inclusion.
Conclusions: Although steroid therapy often cannot be altered in the critically ill population, research showed that steroid overuse is common in intensive care units. Minimizing dosage and duration are important ways clinicians can mitigate AEs.
ICU Steroid Use
Steroids are commonly used in the ICU and affect nearly every critically ill population. Common indications for steroids in the ICU include anaphylaxis, airway edema, septic shock, asthma and COPD exacerbations, pneumocystis pneumonia, adrenal crisis, antiemetic treatment, elevated intracranial pressure from tumors, autoimmune disorders, and stress doses needed for chronic steroid users before invasive procedures.26 Whether divided into glucocorticoid or mineralocorticoid subgroups, corticosteroids offer therapeutic benefit from their pharmacologic similarity to endogenously produced cortisol, which includes anti-inflammatory, immunosuppressive, antiproliferative, and vasoconstrictive effects.
Steroid receptors are present in most human tissue, and in varying degrees of binding affinity produce a wide variety of effects. After passive diffusion across cell membranes, steroid-receptor activation binds to various DNA sites, called glucocorticoid regulatory elements, which either stimulates or inhibits transcription of multiple nearby genes.
At the cellular level, corticosteroids inhibit the release of arachidonic acid through upstream production of lipocortin peptides and antagonism of phospholipase A2. This action decreases subsequent inflammatory mediators, including kinins, histamine, liposomal enzymes, and prostaglandins. Steroids also inhibit NF-κB, which further decreases expression of proinflammatory genes while promoting interleukin-10 and its anti-inflammatory properties. Antiproliferative effects of steroids are seen by triggering cell apoptosis and inhibition of fibroblast proliferation.27,28
By binding to mineralocorticoid receptors, steroids cause sodium retention coupled with hydrogen and potassium excretion in the distal renal tubule. Steroids also promote vasoconstriction by upregulating the production and sensitivity of β receptors in the endothelium while suppressing the production of vasodilators. Although rarely used for these physiologic effects, steroids also are involved in a number of metabolic pathways, including calcium regulation, gluconeogenesis, protein metabolism, and fat distribution. Given the similar structure to cortisol, exogenous steroids depress the hypothalamic-pituitary axis (HPA) and decrease the release of adrenocorticotropic hormone (ACTH). Tapering doses of steroid regimens is often required to allow natural androgen and cortisol synthesis and prevent steroid withdrawal.27,28
The potency of various exogenous steroids closely parallels their ability to retain sodium (Table 2). Prolonged activation of steroid receptors can have numerous systemic AEs, including unwanted neurocognitive effects (Table 3). Insomnia and psychosis are commonly described in corticosteroid clinical trials, and in one meta-analysis, both are associated with high costs per episode per year.29
Steroid-Induced Sleep Disruption and Psychosis
Sleep disruption caused by exogenous administration of steroids is thought to trigger other psychostimulant effects, such as mood swings, nervousness, psychoses, and delirium.30 Similarly, the SCCM PADIS guidelines included an ungraded statement: “although an association between sleep quality and delirium occurrence exists in critically ill adults, a cause-effect relationship has not been established.”17 For this review, these AEs will be discussed as related events.
The medical literature proposes 3 pathways primarily responsible for neurocognitive AEs of steroids: behavior changes through modification of the HPA axis, changes in natural sleep-wake cycles, and hyperarousal caused by modification in neuroinhibitory pathways (Figure).
HPA Axis Modification
Under either physical or psychological stress, neural circuits in the brain release corticotropin-releasing hormone (CRH), dehydroepiandrosterone (DHEA), and arginine vasopressin, which go on to activate the sympathetic nervous system and the HPA axis. CRH from the hypothalamus goes on to stimulate ACTH release from the pituitary. ACTH then stimulates cortisol secretion from the adrenal glands. Circulating cortisol feeds into several structures of the brain, including the pituitary, hippocampus, and amygdala. Steroid-receptor complexes alter gene transcription in the central nervous system (CNS), affecting the production of neurotransmitters (eg, dopamine, serotonin) and neuropeptides (eg, somatostatin, β-endorphin). Feedback inhibition ensues, with downregulation of the HPA axis, which prevents depletion of endogenous production of steroids.31 DHEA has protective effects against excessive cortisol activity, but DHEA secretion declines with prolonged cortisol exposure. Exogenous steroids may have different effects than endogenous steroids, and neurocognitive sequelae stem from disruption and imbalance of these physiologic mechanisms.32,33
