Delirium

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sara Zand, M.D.[2] Pratik Bahekar, MBBS [3]; Vishal Khurana, M.B.B.S., M.D. [4]

Delirium is an acute and relatively sudden (developing over hours to days) decline in attention-focus, perception, and cognition. Delirium is commonly associated with a disturbance of consciousness or reduced clarity of awareness about the environment. The change in cognition including memory deficit, disorientation, language disturbance or the development of a perceptual disturbance may happen with rapid fluctuation course. The concept of delirium has been evolving over centuries. Delirium was first identified in the 16th century. In the second half of the 19th century, delirium was identified by French workers as chaotic thinking and cognitive failure, clouding of consciousness, temporospatial disorientation. The definition of confusion and delirium was established by Chaslin and Bonhoeffer as the stereotyped manifestations of acute brain failure. Delirium is classified on the basis of etiology, duration, and severity. Hyperactive delirium is defined as increased psychomotor activity, which may occur with increased mood lability, agitation, non cooperative attitude towards medical treatment. Hypoactive delirium is explained by a hypoactive level of psychomotor activity, which may exist along with increased lethargy or stupor, inattentiveness and motor slowness and is much more common among ICU admitted patients with severe disease.The exact pathophysiology of delirium is still being investigated. The roles of neurotransmitters like acetylcholine and dopamine seem to be important. It involves disrupted connectivity between cortical and subcortical areas of the brain, especially areas concerned with sleep and awakening. The role of increased inflammatory cytokines has been shown in delirious patients. Delirium may be caused by severe physical or mental illness, or any process which interferes with the normal metabolism or function of the brain such as fever, pain, poison (toxic drug reactions), brain injury, surgery, traumatic shock, severe lack of food or water or sleep, and even withdrawal symptoms of certain drug and alcohol dependent states. In addition, there is an interaction between acute and chronic symptoms of brain dysfunction. Delirious states are more easily produced in people already suffering from underlying chronic brain dysfunction. A very common cause of delirium in elderly people is a urinary tract infection, which is easily treatable with antibiotics. Delirium, like mental confusion, is a very general and nonspecific symptom of organ dysfunction. In addition to many organic causes relating to a structural defect or a metabolic problem in the brain, there are also some psychiatric causes, which may also include a component of mental or emotional stress, mental disease.Delirium is differentiated from other causes cognitive dysfunction such as psychiatric Disorders, dementia. Unlike dementia, the course of delirium is reversible with fluctuation in level of consciousness.The prevalence of delirium is approximately 23,000 per 100,000 hospitalized patients worldwide. Between May 2009 to August 2012, the incidence of delirium was estimated to be 8700 cases per 100,000 African-Americans in Indianapolis. Delirium is more commonly observed among elderly patients, especially age> 65 year-old. Male < 65 year-old are more commonly affected with delirium. Delirium is more commonly observed among Female≥ 85-year-old with medical comorbidities. There is no racial predilection for delirium. Young African-American patients are less likely to develop delirium compared with Caucasians of the same age.Common risk factors associated with delirium include older age, dementia, hypertension, emergency surgery or trauma before ICU admission, mechanical ventilation, metabolic acidosis, delirium on the prior day , coma.The duration of delirium may vary from hours to months. After remission , delirium may increase the risk of functional decline, cognitive dysfunction, and institutional placement, and with higher mortality. Delirium in the elderly, can cause many complications, which may include pneumonia and decubitus ulcers, prolonging hospital stays. Delirium was associated with longer postoperative recovery periods, longer hospital stays, and long-term disability after orthopedic surgery. Common complications associated with delirium include increased mortality, cognitive impairment, longer durations of mechanical ventilation, longer lengths of stay in the ICU. Prognosis is dependent on the severity of delirium, and the 1 year mortality rate of patients with delirium is approximately 10%-26%.The DSM V, and ICD-10 have provided diagnostic criteria for delirium. Definition based on DSM-5 include disturbance in attention and awareness (reduced ability to direct, focus, shift attention and reduced orientation to envinment), initiation of disturbance over a short period of time during several hours or days with fluctuation in severity over a day, disturbance in cognition (memory deficit, disorientation, language, visuospatial ability, perception, disturbance other than evolving neurocognitive disorder, disturbance due to medical condition, substance intoxication, or withdrawal. Other definitions of delirium include disturbance in cognition, impairment of immediate recall and recent memory, disorientation to time, place, person, disturbance in sleep wake cycle, Psychomotor disturbances,emotional disturbances in a period of less than 6 months.Delirium causes impairment in functions, sleep-wake cycle and also has a behavioral component. Common symptoms associated with delirium include altered level of consciousness, inattention, disorientation, hallucination, delusions, agitation, inappropriate speech, sleep–wake disturbances, Symptom fluctuation, emotional disturbance. Subclinical delirium or prodromal delirium may precede by 1 to 3 days prior to an overt delirium, which presents as restlessness, anxiety, irritability, distractibility, sleep disturbance with less severe cognitive impairment in comparison to delirium.It is important to do a thorough physical examination to find out the underlying etiology of delirium. Systemic physical examination includes testing vital signs such as temperature, pulse rate, blood pressure, and respiration and also evaluation of mental status. Patients may seem disoriented with difficulty in sustaining attention, problem in short-term memory, poor insight and impaired judgment.Laboratory findings may differ according to the etiology of delirium. Following investigations are done in delirium: pulse oximetry, electrolytes, blood glucose, liver function tests, blood urea nitrogen, creatinine, vitamin B12 , Folate levels, measurement therapeutic drug levels, urine drug screen for substance use, blood alcohol level, complete blood count, urinalysis, thyroid function testing, erythrocyte sedimentation rate, C-reactive protein, rapid plasma reagin screening for syphilis, acquired immune deficiency syndrome/human immunodeficiency virus (AIDS/HIV) screening.Brain CT scan is helpful in the diagnosis the underlying cause of delirium. Findings on brain CT scan among patients admitted with delirium include: acute or subacute infarct, haemorrhage, abscess, neoplasm, vasculitis, posterior reversible encephalopathy syndrome, encephalitis, acute demyelination, Fat embolism.Brain MRI is valuable tool for diagnosis the underlying cause of delirium when the brain CT scan findings are not informative. The most common finding on brain MRI that was missed by brain CT scan was ischemia.EEG maybe helpful for the diagnosis of delirium. EEG findings associated with delirium include periodic discharges, triphasic waves ,lateralized rhythmic delta ,low voltage/generalized attenuation, theta or delta generalized slowing.The presence of either theta or delta generalized slowing correlated strongly with delirium severity regardless of arousal state (hyper- or hypoactive) and comorbidities.Treatment of delirium involves two main strategies: first, treatment of the underlying presumed acute cause or causes, secondly, optimizing conditions of the brain. This involves ensuring that the patient with delirium has adequate oxygenation, hydration, nutrition, and normal levels of metabolites, so that drug effects are minimized, constipation treated, pain treated, and so on. Detection and management of mental stress are also very important. Therefore, the traditional concept that the treatment of delirium is treating the cause is not adequate. Common medications which are used for treatment of delirium include antipsychotic drugs, benzodiazepines, cholinestrase inhibitors, selective -a2 receptor agonist, melatonin based medications, and ketamine. It is important to prevent delirium as delirium is itself neurotoxic. Delirium is associated with global brain atrophy and white matter disruption. Various non pharmacological and pharmacological interventions are found to be effective to prevent delirium. Primary prevention sterategies for Post-operative [delirium]] include use of haloperidol, second generation antipsychotics, iliac fascia block, lower levels of intraoperative propofol for sedation, continuous intravenous infusion of dexmedetomidine, and use of Melatonin. ketamine is not useful for prevention of postoperative delirium. Preoperative administration of gabapentin is not effective for prevention of postoperative delirium.Secondary prevention strategies following delirium include avoidance of anticholinergic drugs, attention to environmental factors (sensory input, orientation aids, reassuring human contact, routine screening for finding high risk patients, early recognition of any change or fluctuation of mental state or behaviour.

The concept of delirium has been evolving over centuries. Delirium was first identified in the 16th century. In the second half of the 19th century, delirium was identified by French workers as chaotic thinking and cognitive failure, clouding of consciousness, temporospatial disorientation. The definition of confusion and delirium was established by Chaslin and Bonhoeffer as the stereotyped manifestations of acute brain failure.

The exact pathophysiology of delirium is still being investigated. The roles of neurotransmitters like acetylcholine and dopamine seem to be important. It involves disrupted connectivity between cortical and subcortical areas of the brain, especially areas concerned with sleep and awakening. The role of increased inflammatory cytokines has been shown in delirious patients.

Delirium may be caused by severe physical or mental illness, or any process which interferes with the normal metabolism or function of the brain such as fever, pain, poison (toxic drug reactions), brain injury, surgery, traumatic shock, severe lack of food or water or sleep, and even withdrawal symptoms of certain drug and alcohol dependent states. In addition, there is an interaction between acute and chronic symptoms of brain dysfunction. Delirious states are more easily produced in people already suffering from underlying chronic brain dysfunction. A very common cause of delirium in elderly people is a urinary tract infection, which is easily treatable with antibiotics. Delirium, like mental confusion, is a very general and nonspecific symptom of organ dysfunction. In addition to many organic causes relating to a structural defect or a metabolic problem in the brain, there are also some psychiatric causes, which may also include a component of mental or emotional stress, mental disease.

Delirium is differentiated from other causes cognitive dysfunction such as psychiatric Disorders, dementia. Unlike dementia, the course of delirium is reversible with fluctuation in level of consciousness.

The prevalence of delirium is approximately 23,000 per 100,000 hospitalized patients worldwide. Between May 2009 to August 2012, the incidence of delirium was estimated to be 8700 cases per 100,000 African-Americans in Indianapolis. Delirium is more commonly observed among elderly patients, especially age> 65 year-old. Male < 65 year-old are more commonly affected with delirium. Delirium is more commonly observed among Female≥ 85-year-old with medical comorbidities. There is no racial predilection for delirium. Young African-American patients are less likely to develop delirium compared with Caucasians of the same age.

Common risk factors associated with delirium include older age, dementia, hypertension, emergency surgery or trauma before ICU admission, mechanical ventilation, metabolic acidosis, delirium on the prior day , coma.

The duration of delirium may vary from hours to months. After remission , delirium may increase the risk of functional decline, cognitive dysfunction, and institutional placement, and with higher mortality. Delirium in the elderly, can cause many complications, which may include pneumonia and decubitus ulcers, prolonging hospital stays. Delirium was associated with longer postoperative recovery periods, longer hospital stays, and long-term disability after orthopedic surgery. Common complications associated with delirium include increased mortality, cognitive impairment, longer durations of mechanical ventilation, longer lengths of stay in the ICU. Prognosis is dependent on the severity of delirium, and the 1 year mortality rate of patients with delirium is approximately 10%-26%.

The DSM V, and ICD-10 have provided diagnostic criteria for delirium. Definition based on DSM-5 include disturbance in attention and awareness (reduced ability to direct, focus, shift attention and reduced orientation to envinment), initiation of disturbance over a short period of time during several hours or days with fluctuation in severity over a day, disturbance in cognition (memory deficit, disorientation, language, visuospatial ability, [[perception, disturbance other than evolving neurocognitive disorder, disturbance due to medical condition, substance intoxication, or withdrawal. Other definitions of delirium include disturbance in cognition, impairment of immediate recall and recent memory, disorientation to time, place, person, disturbance in sleep wake cycle, Psychomotor disturbances,emotional disturbances in a period of less than 6 months.

Delirium causes impairment in functions, sleep-wake cycle and also has a behavioral component. Common symptoms associated with delirium include altered level of consciousness, inattention, disorientation, hallucination, delusions, agitation, inappropriate speech, sleep–wake disturbances, Symptom fluctuation, emotional disturbance. Subclinical delirium or prodromal delirium may precede by 1 to 3 days prior to an overt delirium, which presents as restlessness, anxiety, irritability, distractibility, sleep disturbance with less severe cognitive impairment in comparison to delirium

It is important to do a thorough physical examination to find out the underlying etiology of delirium. Systemic physical examination includes testing vital signs such as temperature, pulse rate, blood pressure, and respiration and also evaluation of mental status. Patients may seem disoriented with difficulty in sustaining attention, problem in short-term memory, poor insight and impaired judgment.

Laboratory findings may differ according to the etiology of delirium. Following investigations are done in delirium: pulse oximetry, electrolytes, blood glucose, liver function tests, blood urea nitrogen, creatinine, vitamin B12 , Folate levels, measurement therapeutic drug levels, urine drug screen for substance use, blood alcohol level, complete blood count, urinalysis, thyroid function testing, erythrocyte sedimentation rate, C-reactive protein, rapid plasma reagin screening for syphilis, acquired immune deficiency syndrome/human immunodeficiency virus (AIDS/HIV) screening.

Brain CT scan is helpful in the diagnosis the underlying cause of delirium. Findings on brain CT scan among patients admitted with delirium include: acute or subacute infarct, haemorrhage, abscess, neoplasm, vasculitis, posterior reversible encephalopathy syndrome, encephalitis, acute demyelination, Fat embolism.

Brain MRI is valuable tool for diagnosis the underlying cause of delirium when the brain CT scan findings are not informative. The most common finding on brain MRI that was missed by brain CT scan was ischemia.

EEG maybe helpful for the diagnosis of delirium. EEG findings associated with delirium include periodic discharges, triphasic waves ,lateralized rhythmic delta ,low voltage/generalized attenuation, theta or delta generalized slowing.The presence of either theta or delta generalized slowing correlated strongly with delirium severity regardless of arousal state (hyper- or hypoactive) and comorbidities.

Treatment of delirium involves two main strategies: first, treatment of the underlying presumed acute cause or causes, secondly, optimizing conditions of the brain. This involves ensuring that the patient with delirium has adequate oxygenation, hydration, nutrition, and normal levels of metabolites, so that drug effects are minimized, constipation treated, pain treated, and so on. Detection and management of mental stress are also very important. Therefore, the traditional concept that the treatment of delirium is treating the cause is not adequate. Common medications is used for delirium treatment include antipsychotic drugs, benzodiazepines, cholinestrase inhibitors, selective -a2 receptor agonist, melatonin based medications, ketamine.

It is important to prevent delirium as delirium is itself neurotoxic. Delirium is associated with global brain atrophy and white matter disruption. Various non pharmacological and pharmacological interventions are found to be effective to prevent delirium. Primary prevention sterategy for Post-operative delirium may include use of haloperidol, second generation antipsychotics, iliac fascia block, lower levels of intraoperative propofol for sedation, continuous intravenous infusion of dexmedetomidine,and use of Melatonin. ketamine is not useful in preventing postoperative delirium. Preoperative administration of gabapentin is not effective for prevention of postoperative delirium.

Secondary prevention strategies following delirium include avoid anticholinergic drugs, attend to environmental factors (sensory input, [[orientation aids], reassuring human contact, routine screening for finding high risk patients, early recognition of any change or fluctuation of mental state or behaviour.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sara Zand, M.D.[2] Pratik Bahekar, MBBS [3]; Vishal Khurana, MBBS, MD [4]

The exact pathophysiology of delirium is still being investigated. The roles of neurotransmitters like acetylcholine and dopamine seem to be important. It involves disrupted connectivity between cortical and subcortical areas of the brain, especially areas concerned with sleep and awakening. The role of increased inflammatory cytokines has been shown in delirious patients.

• Acetylcholine has a crucial role in sleep, attention, arousal, and memory.
• Dopamine is involved in the regulation of acetylcholine.
• Reduced acetylcholine and histamine activity and increased dopamine and glutamate activity are observed in delirium.^[1]
• Roles of GABA and serotonin are uncertain.^[2]
• Anticholinergics are known to predispose to delirium and at the same time, anti dopaminergics are known to curtail delirium.
• Cortical and subcortical dysfunctions are behind the development of delirium.
• Disrupted connectivity is a key feature in delirium and it is observed in the following neuronal connections:

• The dorsal lateral prefrontal cortex and the posterior cingulate cortex
• Intralaminar thalamus from brainstem and midbrain nuclei

• Midbrain nucleus basalis is a source of cholinergic activation, whereas the midbrain ventral tegmental area is a source of dopaminergic innervation.
• Mesencephalic tegmentum and the thalamus are linked to the early restoration of alertness.
• Subcortical connections tend to recover sooner than the cortical connection.^[3]
• Individuals with brain abnormalities like cortical atrophy, ventricular enlargement, and increased white matter lesions are more likely to develop delirium.^[4]
• Anticholinergic drugs such as biperiden and scopolamine may have hypocholinergic delirium-like effects.^[5]
• Profound systemic inflammation occurring during bacteremia or sepsis may cause delirium (often termed septic encephalopathy).
• Study showed even mild systemic inflammation, a frequent trigger for clinical delirium, induces acute and transient attentional or working memory deficits, but only in animals with prior pathology.^[6]
• Prior dementia or age-associated cognitive impairment is the primary predisposing factor for clinical delirium.

• A few studies have exploited the opportunity to sample CSF from persons undergoing spinal anesthesia for elective or emergency surgery.^[7]
• Delirium may be associated with increased serotoninergic and dopamine signaling, decreased somatostatin, increased cortisol, increase in some inflammatory cytokines (IL-8), but not others (TNF-α, IL-1β).
• Postoperative delirium was strongly associated with pre-operative cognitive decline.^[8]
• However, CSF Aβ1-42, tau, and phosphorylated tau levels were not associated with delirium status, nor did they correlate significantly with cognitive function

• Delirium duration was related to measures of white matter tract integrity and this, in turn, was related to poorer cognitive outcomes at 3 and 12 months.^{[9] [10]}
• Brain volumes were also assessed and related to cognitive outcomes in the same manner.
• Longer duration of delirium was associated with smaller brain volume and more white matter disruption, and both these correlated with worse cognitive scores 12 months later.
• Study showed that white matter damage predicted post-operative delirium.^[11][12]
• One functional MRI study reported a reversible reduction in activity in brain areas localizing with cognition and attention function.^[13][14]

• Finding of Autopsy of ICU admitted patients in a study showed evidence of acute respiratory distress syndrome, septic shock, hypoperfusion and diffuse vascular injury, with consistent involvement of the hippocampus.^[15]
• The role of inflammatory cytokine has been shown in delerious patients.^[16]
• Persons with delirium had higher scores for HLA-DR and CD68 (markers of microglial activation), IL-6 (cytokines pro-inflammatory and anti-inflammatory activities) and GFAP (marker of astrocyte activity).

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