It is also possible that the same inflammatory mediators trigger reactive oxygen species and widespread glial activation affecting nearly all cerebral networks simultaneously, including those regulating sleep and circadian function. For example, it is possible that inflammatory mediators of sepsis preferentially affect key nuclei of the hypothalamic–pituitary axis, resulting in disruptions to the sleep regulation cycle, and leading to widespread cortical dysfunction that manifests as delirium. Poor sleep can be developed through many factors such as neurotransmitter dysregulation, aging, and hormones.79 The complexity of these interactions may be key to understanding how age, preexisting neuropathological conditions, and pharmacological interventions may contribute to increased susceptibility to dementia in some populations.80 Extensive pretraining in an operant task prior to surgical bone break demonstrated changes in attentional function.77 Of particular interest and importance are behavioral indices that recapitulate changes observed in humans. Another important approach is to explore the role of commonly used pharmaceutical interventions such as atropine, which is known for side effects of delirium and hallucinations.75 In addition to treatments, the environment of the ICU itself can impact patient response, as has been modeled by reproducing sleep disturbance.76 Animal models have been useful for studying perioperative delirium, as there is more control over timing to study biomarkers to compare pre- and postsurgery outcomes. The ability to use animal models offers important tools to better understand the mechanistic underpinnings of delirium as they relate to clinical observations and potential therapeutic interventions (►Fig. 3).
Mixed delirium
An underactive thyroid gland (hypothyroidism) causes delirium with sluggishness (lethargy). In older adults, prescription medications are usually the cause. In younger people, using recreational or illicit drugs and acute intoxication with alcohol are common causes. Delirium may also develop when people who are about to have surgery do not have access to a substance they have been using, such as a recreational or illicit drug, alcohol, or tobacco. Sleep is disturbed by staff members who awaken people during the night to monitor and treat them and by loud beeping monitors, intercoms, voices in the hallway, and alarms.
Intensive care unit
The systematic review estimated a 13-fold increase in dementia after delirium (meta-analysis of two studies). In a community-based population examining individuals after an episode of severe infection (though not specifically delirium), these persons acquired more functional limitations (i.e., required more assistance with their care needs) than those not experiencing infection. This systematic review only included studies that looked for an independent effect of delirium (i.e., after accounting for other associations with poor outcomes, for example co-morbidity or illness severity). There is substantial evidence that delirium results in long-term poor outcomes in older persons admitted to hospital. Low quality evidence indicates that the antipsychotic medications risperidone or haloperidol may make the delirium slightly worse in people who are terminally ill, when compared to a placebo treatment.
Impact of medications
Some estimates suggest that up to two-thirds of cases of delirium in hospital settings are missed or misdiagnosed. Since many conditions share similar symptoms, the sudden onset of delirium helps distinguish it from other disorders that develop more gradually. The chart below highlights the key differences between delirium and dementia.
Challenges in fully interpreting the current data include limited studies that share clinical triggers, varied clinical populations, and small sample sizes. Recent evidence points to several promising avenues for investigation including interleukin-6 (IL-6), C-reactive protein (CRP), S100B, and insulin-like growth factor (IGF), identified from individual studies and meta-analyses.34 Though these represent only a small subset of the wide range of biomarkers studied to date as potential correlates (►Table 1),35,36 together these biomarkers Delirium Tremens Symptoms strongly implicate the acute inflammatory and cellular metabolism response in both neural and peripheral tissues as potentially causative in delirium. Taken together, these findings suggest alterations in temporal and spatial patterns of activity, globally as well as interactions among disparate regions of the brain, play a significant role in the manifestations of delirium, and likely in its development. As levels of cognitive functioning diminished, they observed more generalized slowing (delta activity) on the EEG traces, and this activity normalized with the administration of oxygen or other treatments to improve cognitive function.22,23 The authors concluded that delirium was likely a syndrome of cerebral insufficiency, wherein the metabolic supply of the neural tissue was inadequate to support normal function.24 In sum, neuroimaging studies to date suggest that delirium is characterized by widespread decreases in cerebral metabolism and disruption in structural and dynamic connectivity of cerebral networks important for attention, arousal (maintaining wakefulness), and introspection.
We briefly review how clinical observational studies support the previously proposed “common denominator” pathway of systems integration failure.1 We discuss how emerging animal models of delirium will allow the opportunity to refine this understanding. Elevated serum biomarkers of inflammation, including interleukin-6, C-reactive protein, and S100B, suggest a role of dysregulated inflammatory processes and cellular metabolism, particularly in perioperative and sepsis-related delirium. Delirium and dementia can exist at same time but they are not the same medical syndrome. Hospitals can help lower the risk of delirium by avoiding sedatives and making sure that hospital rooms are kept quiet, calm, and well-lit. About 30 to 50% of people who have delirium while in a hospital die within 1 year, but the cause of death is often another serious disorder, not delirium itself.
Prevention
Delirium can result from less severe conditions in older adults and in people who have had a stroke or who have dementia, Parkinson disease, or brain damage due to another condition. Delirium often develops during hospitalization in people who have dementia. Any person can become delirious when extremely ill or taking medications or drugs that affect brain function (psychoactive medications or drugs). In such cases, medical attention is needed immediately because delirium may be caused by a serious disorder.
Poor thinking skills
Aged mice experience a higher production of proinflammatory cytokines within the brain after receiving LPS compared to young adult animals, leading to more severe sickness. Surgical methods include cecal ligation puncture, tibial fracture, and ischemia-reperfusion, while injection methods include cecal slurry, LPS, atropine, cytokines (IL-1β, TNF-α), and neurotoxins. A schematic representation of inducing delirium in animal models (left half) and outcomes to measure a delirium-like state in animal models (right half). Key examples include POD,68 treatment with lipopolysaccharides (LPS) to model inflammatory response,69,70 and polymicrobial sepsis through surgical (cecal ligation and puncture)71,72 and nonsurgical (cecal slurry) 73,74 approaches.
Who is more likely to get delirium?
Delirium may be confused with multiple psychiatric disorders or chronic organic brain syndromes because of many overlapping signs and symptoms in common with dementia, depression, psychosis, etc. Delirium may be difficult to diagnose without first establishing a person’s usual mental function or ‘cognitive baseline’. Any condition that results in a hospital stay increases the risk of delirium. However, episodes of delirium don’t always mean a person has dementia.
Disorders
Electroencephalography (EEG) allows for continuous capture of cortical activity in the brain, and is useful in understanding real-time physiologic changes during delirium. Along with clinical studies using various drugs with anticholinergic activity, these models have contributed to a “cholinergic deficiency hypothesis” of delirium. In medical terminology, however, the core features of delirium include an acute disturbance in attention, awareness, and global cognition. If a relative, friend or someone in your care shows symptoms of delirium, talk to the person’s health care provider.
- A person may have trouble paying attention, feel disoriented, or even see or hear things that aren’t really there (hallucinations).
- While requiring an acute disturbance in attention, awareness, and cognition, the syndrome of delirium encompasses a broad range of additional neuropsychiatric disturbances.
- In prospective studies, people hospitalised from any cause appear to be at greater risk of dementia and faster trajectories of cognitive decline, but these studies did not specifically look at delirium.
- Sudden confusion about time and often about place (where they are) may be an early sign of delirium.
This leads to a disproportionate number of individuals who experience delirium being from marginalized identities. Based on socioeconomic classes, this may be valuable time that would be used working to support the family. Alternative effective delirium prevention programs have been developed, some of which do not require volunteers. There are two working parts to this program, medical professionals such as a trained nurse, and volunteers, who are overseen by the nurse. HELP prevents delirium among the elderly through active participation and engagement with these individuals. In 1999, Sharon K. Inouye at Yale University, founded the Hospital Elder Life Program (HELP) which has since become recognized as a proven model for preventing delirium.
- (D-I) FDG-PET hypometabolism in bilateral frontal, parietal, and temporal cortices during delirium (D–F) with relative sparing of the sensorimotor cortex (dotted arrows), and reversal after delirium resolution (G–I).
- For inpatients in a hospital setting, numerous approaches have been suggested to prevent episodes of delirium including targeting risk factors such as sleep deprivation, mobility problems, dehydration, and impairments to a person’s sensory system.
- Dexmedetomidine may shorten the length of the delirium in adults who are critically ill, and rivastigmine is not suggested.
- Treatment may slow the mental decline in people with dementia but usually cannot stop the decline.
- Neuroimaging modalities such as magnetic resonance imaging (MRI), positron emission tomography, functional MRI, and near-infrared spectroscopy point to global atrophy, white matter changes, and disruptions in cerebral blood flow, oxygenation, metabolism, and connectivity as key correlates of delirium pathogenesis.
- Both can cause confusion, memory problems, agitation, and difficulty with speech, and some people may have both at the same time.
For children in need of intensive care there are validated clinical tools adjusted according to age. Delirium detection in general acute care settings can be assisted by the use of validated delirium screening tools. There is evidence that delirium detection and coding rates can show improvements in response to guidelines and education; for example, whole country data in England and Scotland (sample size 7.7M people per year) show that there were large increases (3-4 fold) in delirium coding between 2012 and 2020. A systematic review of large scale routine data studies reporting data on delirium detection tools showed important variations in tool completion rates and tool positive score rates. However, early recognition of delirium’s features using screening instruments, along with taking a careful history, can help in making a diagnosis of delirium. Each case was admitted with a range of primary pathologies, but all had acute respiratory distress syndrome and/or septic shock contributing to the delirium, 6 showed evidence of low brain perfusion and diffuse vascular injury, and 5 showed hippocampal involvement.
Health care providers may rely on input from a family member or caregiver to diagnose the disorder. Factors may include a severe or long illness or an imbalance in the body, such as low sodium.
Emerging animal models that can mimic delirium-like clinical states will reveal further insights into delirium pathophysiology. Electroencephalography demonstrates generalized slowing of normal background activity, with pathologic decreases in variability of oscillatory patterns and disruptions in functional connectivity among specific brain regions. Delirium affects approximately 18% to 25% of hospital inpatients, with even higher rates observed during critical illness. Delirium is a major disturbance in the mental state characterized by fluctuations in arousal, deficits in attention, distorted perception, and disruptions in memory and cognitive processing.
The lack of animal models that are relevant to delirium has left many key questions in delirium pathophysiology unanswered. Although slight differences exist between the definitions of delirium in the DSM-5-TR and ICD-10, the core features are broadly the same. In common usage, delirium can refer to drowsiness, agitation, disorientation, or hallucinations.
(B) Enlarged ventricles in a 42-year-old female with community-acquired pneumonia, who required mechanical ventilation in the ICU and whose ICU course was complicated by 12 days of delirium. In this article, we discuss key observations from neuroimaging, neurophysiology, and blood biomarker studies. These, combined with knowledge of the predisposing and precipitating factors leading to delirium, have resulted in diverse observations and hypotheses regarding the principal mechanistic processes underpinning this disorder. Successful development of targeted treatments for delirium hinges on the characterization of the physiological mechanisms by which it develops and is sustained. Neuroimaging modalities such as magnetic resonance imaging (MRI), positron emission tomography, functional MRI, and near-infrared spectroscopy point to global atrophy, white matter changes, and disruptions in cerebral blood flow, oxygenation, metabolism, and connectivity as key correlates of delirium pathogenesis. To develop therapies to shorten the duration and limit the adverse effects of delirium, it is important to understand the mechanisms underlying its presentation.
Other symptoms also often change within minutes and tend to worsen during the evening (a phenomenon called sundowning). That is, people may be overly alert one moment and drowsy and sluggish the next. People with delirium cannot concentrate, so they have trouble processing new information and cannot recall recent events.
Friends, family members, or other observers are asked for information because people with delirium are usually unable to answer. Doctors do so by collecting as much information about the person’s medical history as possible, by doing a physical examination, and by testing. However, mild delirium may be difficult to recognize. People with delirium often sleep restlessly or reverse their sleep-wake cycle, sleeping during the day and staying awake at night. If delirium is severe, people may not know who they or other people are. Doctors try to distinguish the 2 by determining how quickly the confusion developed and what the person’s previous mental function was.