Materiały źródłowe

• #1 Delirium: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/288890-overview

  Delirium is typically a transient global disorder of cognition; however, growing evidence shows that this is not always true. […] The mechanism of delirium still is not fully understood. Delirium results from a wide variety of structural or physiological insults. The neuropathogenesis of delirium has been studied in patients with hepatic encephalopathy and alcohol withdrawal. Research in these areas is limited. The main hypothesis is reversible impairment of cerebral oxidative metabolism and multiple neurotransmitter abnormalities. The following observations support the hypothesis of multiple neurotransmitter abnormalities. […] Data from animal and clinical studies support the hypothesis that acetylcholine is one of the critical neurotransmitters in the pathogenesis of delirium. […] In the brain, a reciprocal relationship exists between cholinergic and dopaminergic activities. In delirium, an excess of dopaminergic activity occurs.

• #2 Unravelling the pathophysiology of delirium: a focus on the role of aberrant stress responses

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4311661/

  Delirium is a common and serious acute neuropsychiatric syndrome with core features of inattention and cognitive impairment, and associated features including changes in arousal, altered sleep-wake cycle, and other changes in mental status. […] The molecular mechanisms by which these precipitating factors lead to delirium are largely obscure. In this article we attempt to narrow down some specific causal pathways. […] We propose a basic classification for the aetiological factors: (a) direct brain insults, and (b) aberrant stress responses. […] Aberrant stress responses are conceptually and mechanistically distinct in that they constitute adverse effects of stress-response pathways which, in health, are adaptive. […] We discuss in detail two stress response systems that are likely to be involved in the pathophysiology of delirium: inflammation and the sickness behaviour response, and activity of the limbic-hypothalamic-pituitary-adrenal axis.

• #3 Delirium | Nature Reviews Disease Primers

  https://www.nature.com/articles/s41572-020-00223-4

  Delirium, a syndrome characterized by an acute change in attention, awareness and cognition, is caused by a medical condition that cannot be better explained by a pre-existing neurocognitive disorder. […] Because multiple factors are implicated in the aetiology of delirium, there are likely several neurobiological processes that contribute to delirium pathogenesis, including neuroinflammation, brain vascular dysfunction, altered brain metabolism, neurotransmitter imbalance and impaired neuronal network connectivity. […] Pharmacological treatments for delirium (such as antipsychotic drugs) are not effective, reflecting substantial gaps in our understanding of its pathophysiology. […] This perspective piece gathers many key observations on clinical and volunteer neurophysiology studies detailing the relationship between EEG and delirium symptoms as well as making a compelling case for the role of disturbed brain energy metabolism as a driver of delirium.

• #4 Delirium – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK470399/

  Delirium is a manifestation of stress on the function of the central nervous system in a vulnerable patient. The pathophysiology is not fully understood, and there is likely no single etiology. Multiple theories describe the potential pathophysiologic causes of delirium, and any single case of delirium probably involves one or more of these theories in a complex and interconnected process. Multifactorial models have been accepted, describing delirium as an interaction of a vulnerable patient with predisposing factors exposed to noxious insults or precipitant factors. […] There is no single mechanism to explain the etiology of delirium. It is a complicated and multifactorial process. Several hypotheses describe different aspects of the pathophysiology of delirium, and multiple processes are likely to occur simultaneously to create the delirium syndrome.

• #5 Phenotypes and subphenotypes of delirium: a review of current categorisations and suggestions for progression | Critical Care | Full Text

  https://ccforum.biomedcentral.com/articles/10.1186/s13054-021-03752-w

  Delirium is a clinical syndrome occurring in heterogeneous patient populations. […] Despite an exponential rise in delirium research, understanding of the pathophysiological processes underlying delirium remains low. […] Identifying specific clinical and biological subphenotypes will greatly improve understanding of the relationship between the clinical symptoms and the putative pathways and thus risk factors, precipitants, natural history, and biological mechanism. […] Classification of delirium based on expression markers or biological data may provide insight into its underlying mechanisms, potentially leading to more ambitious targeted treatments which are not possible with reliance on classification by clinical traits only. At least six neuropathophysiological hypotheses, which remain poorly understood, have been proposed to precipitate delirium.

• #6

  https://scitemed.com/article/2687/Epidemiology,-Mechanisms,-Diagnosis,-and-Treatment-of-Delirium-A-Narrative-Review

  Delirium is an acute disorder of arousal and attention that is commonly encountered, incompletely understood, and associated with adverse outcomes including increased morbidity and mortality, reduced health-related quality of life, and increased healthcare costs. […] While not fully understood, delirium is characterized by widespread dysfunction in inflammation, neurotransmitter and neurohormonal signaling, and structural abnormalities within the blood-brain barrier and brain parenchyma. […] The pathophysiology of delirium is complex, multifactorial, and incompletely understood, with multiple different mechanisms contributing to the symptoms of this clinical syndrome. Several abnormalities have been described and different hypotheses developed to explain the changes in arousal, cognition, and perception that are the hallmarks of this disorder.

• #7 Delirium – Neurologic Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/neurologic-disorders/delirium-and-dementia/delirium

  Mechanisms are not fully understood but may involve […] Reversible impairment of cerebral oxidative metabolism […] Multiple neurotransmitter abnormalities, especially cholinergic deficiency […] Generation of inflammatory markers, including C-reactive protein, interleukin-1 beta and 6, and tumor necrosis factor-alpha […] Stress of any kind upregulates sympathetic tone and downregulates parasympathetic tone, impairing cholinergic function and thus contributing to delirium. Older adults are particularly vulnerable to reduced cholinergic transmission, increasing their risk of delirium. […] Regardless of the cause, the cerebral hemispheres and arousal mechanisms of the thalamus and brain stem reticular activating system become impaired.

• #8 Phenotypes and subphenotypes of delirium: a review of current categorisations and suggestions for progression | Critical Care | Full Text

  https://ccforum.biomedcentral.com/articles/10.1186/s13054-021-03752-w

  The neuroinflammation hypothesis may allow for categorisation into inflammatory or neuroinflammatory, and non-inflammatory delirium, as the biomarkers may differ depending on presence of inflammation. […] The neuronal ageing hypothesis may be observed by examination of brain volume using tools such as molecular resonance imaging which may aid in subphenotype identification. […] The oxidative stress hypothesis is derived from evidence of increased hippocampal reactive oxygen species (ROS) associated with delirium during in vivo study. […] The neurotransmitter hypothesis incorporates the serotonergic, dopaminergic, and cholinergic systems. […] The melatonin dysregulation hypothesis suggests that some of the difference in delirium symptoms could be associated with melatonin levels. […] The network dysconnectivity hypothesis suggests that the clinically expressed symptoms of delirium may be attributable to disruption of functional networks in the brain and altered homeostasis of neural oscillation.

• #9 Pathogenesis of Delirium | SpringerLink

  https://link.springer.com/chapter/10.1007/978-3-319-65239-9_2

  Delirium is a complex syndrome defined as an acute, fluctuating syndrome of altered attention, awareness, and cognition. […] However, evidence that delirium is a neurotoxic factor which develops due primarily to neurotransmitter (cholinergic insufficiency) and inflammatory (increase in stress response/neuroinflammation) mechanisms is increasing each passing day. […] In addition, changes in neuronal injury and permeability of blood-brain barrier, impairment in sleep pattern, genetic, and drugs may play a role in the development of delirium.

• #10 Phenotypes and subphenotypes of delirium: a review of current categorisations and suggestions for progression | Critical Care | Full Text

  https://ccforum.biomedcentral.com/articles/10.1186/s13054-021-03752-w

  Delirium is a clinical syndrome occurring in heterogeneous patient populations. […] Despite an exponential rise in delirium research, understanding of the pathophysiological processes underlying delirium remains low. […] Identifying specific clinical and biological subphenotypes will greatly improve understanding of the relationship between the clinical symptoms and the putative pathways and thus risk factors, precipitants, natural history, and biological mechanism. […] Classification of delirium based on expression markers or biological data may provide insight into its underlying mechanisms, potentially leading to more ambitious targeted treatments which are not possible with reliance on classification by clinical traits only. At least six neuropathophysiological hypotheses, which remain poorly understood, have been proposed to precipitate delirium.

• #11 Delirium: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/288890-overview

  Delirium is typically a transient global disorder of cognition; however, growing evidence shows that this is not always true. […] The mechanism of delirium still is not fully understood. Delirium results from a wide variety of structural or physiological insults. The neuropathogenesis of delirium has been studied in patients with hepatic encephalopathy and alcohol withdrawal. Research in these areas is limited. The main hypothesis is reversible impairment of cerebral oxidative metabolism and multiple neurotransmitter abnormalities. The following observations support the hypothesis of multiple neurotransmitter abnormalities. […] Data from animal and clinical studies support the hypothesis that acetylcholine is one of the critical neurotransmitters in the pathogenesis of delirium. […] In the brain, a reciprocal relationship exists between cholinergic and dopaminergic activities. In delirium, an excess of dopaminergic activity occurs.

• #12 Delirium – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK470399/

  Delirium is associated with decreased acetylcholine and increased dopamine activity. The brain’s dopaminergic and cholinergic pathways overlap, and their balance is vital to brain function. […] Increased glucocorticoid release in response to physiologic stress increases the vulnerability of neurons to subsequent damage and impacts the regulation of gene transcription, cellular signaling, and glial cell behavior.

• #13 Prevention and management of delirium in critically ill adult patients in the intensive care unit: a review based on the 2018 PADIS guidelines

  https://www.accjournal.org/journal/view.php?doi=10.4266/acc.2019.00451

  PATHOGENESIS The biological basis of delirium and confusion remains poorly understood, in part because it is difficult to evaluate severely ill patients using conventional electrophysiologic tests, brain imaging, and neurotransmitter assays. Furthermore, proposed animal models of delirium are not well-developed or validated at this time. Despite these limitations, some important results about the pathophysiology of delirium have been reported to date. First, imbalances or derangements of multiple neurotransmitter systems have been implicated in the pathophysiology of delirium. Cerebrospinal fluid studies of patients with delirium reveal alterations in neuropeptides. Acetylcholine is one of the major neurotransmitters involved in ascending reticular activating system function and plays a key role in the pathogenesis of delirium. A reduction in cholinergic function leads to increased levels of glutamate, dopamine, and norepinephrine in the brain. Decreased serotonin and gamma-aminobutyric acid levels also possibly contribute to the pathogenesis of delirium. Anticholinergic drugs cause delirium when given to healthy volunteers and are even more likely to lead to acute confusion in the elderly. With respect to hyper- or hypoactive delirium, dopamine excesses may contribute to hyperactive delirium, which has been linked with simultaneous acetylcholine decreases. Thus, acetylcholine and dopamine may be inversely related in delirium pathogenesis; pharmacological and neuroanatomical evidence also support this model. Separately, norepinephrine plays an important role in modulating attention, anxiety, and mood; like dopamine, excess noradrenergic activity has been associated with hyperactive delirium. Inflammatory mediators (e.g., cytokines, chemokines) are readily expressed during critical illness, trauma, and sepsis and following surgical intervention. Sepsis, severe sepsis, and septic shock are characterized by significantly elevated C-reactive protein, S-100 protein, and cortisol levels in patients with delirium versus without. Proinflammatory cytokines (e.g., tumor necrosis factor-, interleukin-1 family cytokines) and chemokines are associated with endothelial damage in the central nervous system, thrombin formation, and microvascular dysfunction; importantly, these events can result in delirium. A study of ICU patients found that higher levels of procalcitonin at the time of ICU admission are associated with prolonged durations of brain dysfunction. Trends in higher levels of C-reactive protein also suggest a possible association with delirium. However, it is difficult to exclude the confounding effects of underlying illness or dementia. […] Delirium is associated with high perioperative plasma cortisol levels in patients undergoing coronary artery bypass graft surgery and systemic corticosteroid treatment in patients with acute lung injury.

• #14 Polypharmacy Induced Delirium: A Case Report Highlighting the Importance of a Thorough Psychiatric History and Physical

  https://www.jneuropsychiatry.org/peer-review/polypharmacy-induced-delirium-a-case-report-highlighting-the-importance-of-a-thorough-psychiatric-history-and-physical-13118.html

  Poly-pharmacy was ruled in as the etiology of the delirium highlighting the importance of careful prescribing especially in older persons. […] The authors also contend that because delirium is a multifactorial disorder, and psychotropic medications can be dangerous, expert psychiatric consultation is required. […] Delirium is a very common medical condition encountered throughout the world and is one of the most frequent reasons psychiatrists are consulted. […] Psychiatrists understand the neurotransmitters most strongly implicated in delirium pathogenesis such as acetylcholine and dopamine. […] While decreased acetylcholine and anticholinergic activity is presumed to play a role in delirium, hyperactivity in the dopamine system is also implicated in the pathogenesis of delirium. […] Excess glutamate activity or decreased histamine activity also may be etiologic factors in delirium, and certain psychotropic medications involve these neurotransmitters.

• #15 Delirium: Clinical Manifestation and Management In The Emergency Department | RECAPEM

  https://recapem.com/delirium-clinical-manifestation-and-management-in-the-emergency-department/

  Key structures in maintaining an awake state and awareness involve the ascending reticular activating system (ARAS) from the mid-pontine tegmentum rostrally to the thalamus and the anterior cingulate regions, and cortical association area (precuneus and cuneus). […] The results of brainstem auditory evoked potential, somatosensory evoked potentials, and neuroimaging studies have supported an important role for subcortical (eg, thalamus, basal ganglia, and pontine reticular formation) as well as cortical structures in the pathogenesis of delirium. […] Neurotransmitters such as acetylcholine, serotonin, gamma-aminobutyric acid (GABA), and dopamine become imbalanced in delirium, which results in the inability of delirious patients to process information and respond appropriately. […] Acetylcholine plays a key role in the pathogenesis of delirium.

• #16 Delirium in older adults: Diagnosis, prevention, and treatment | British Columbia Medical Journal

  https://bcmj.org/articles/delirium-older-adults-diagnosis-prevention-and-treatment

  Delirium may be due to inflammatory mechanisms and a cholinergic neurotransmitter deficiency in the brain. […] The pathogenesis behind delirium is not fully understood, but several mechanisms have been postulated. Systemic inflammatory cytokine response and neurotransmitter disruption are the two main mechanisms thought to link multifactorial medical conditions and delirium. […] During a systemic inflammatory response such as sepsis, proinflammatory cytokines released in the peripheral circulation enter the central nervous system, altering endothelial function, diminishing perfusion, activating microglia, and causing neuronal apoptosis and neurotoxicity. […] Anticholinergic medications are known to induce or worsen delirium by binding to nicotinic and muscarinic receptors in the brain, modulating cognition and arousal, and lending support to the concept of cholinergic deficiency in delirium.

• #17

  https://link.springer.com/article/10.1007/s00134-018-5276-8

  Haloperidol, the neuroleptic agent par excellence, was synthesized 60 years ago in February 1958. […] This hypothesis also provides a biological basis to explain the observed efficacy of haloperidol not only in schizophrenia but also in delirium. Dopamine excess may cause some of the neurobehavioral alterations observed in patients with hyperactive or mixed type delirium, namely agitation, restlessness, irritability, increased psychomotor activity, distractibility, hyperalertness, combativeness, and psychotic distressing symptoms. […] Dopamine D2 antagonists enhance acetylcholine release, which may be another mechanism by which these drugs help to alleviate the symptoms of delirium. […] The neuroinflammatory hypothesis proposes that systemic inflammation causes increased amounts of pro-inflammatory cytokines and inflammatory mediators to penetrate into the brain, causing neuronal dysfunction and subsequent neurobehavioral and cognitive symptoms of delirium, either directly or by stimulating the microglia to produce inflammatory mediators.

• #18 Assessment of delirium – Differential diagnosis of symptoms | BMJ Best Practice

  https://bestpractice.bmj.com/topics/en-gb/241

  Other neurotransmitters implicated in the pathophysiology of delirium include noradrenaline, serotonin, gamma-aminobutyric acid, glutamate, and melatonin. […] Evidence also points to the role of cytokines such as interleukins 1 and 2 and TNF-alpha and interferon in contributing to delirium. […] Finally, chronic hypercortisolism, as induced by chronic stress secondary to illness or trauma, may also contribute to delirium initiation.

• #19 [Pathophysiology of delirium]. « metajournal.com

  https://www.metajournal.com/articles/137416

  Today’s understanding of the pathophysiological mechanisms of delirium is still limited, but there are several promising hypotheses. […] It is believed that biomarkers sensitive to death of neurons or glial cells indicate delirium. […] Several neurotransmitters are considered to be involved in the state of delirium, with greatest emphasis on acetylcholine and dopamine acting in opposite ways; acetylcholine reduces, while dopamine increases neuron excitability. […] Other neurotransmitters that probably play a role in the pathogenesis of delirium are GABA, glutamate and monoamines. […] Sepsis leading to systemic inflammatory response syndrome often presents with delirium and perhaps is the most common causal factor for delirium in intensive care unit; sedatives and analgesics are also common iatrogenic risk factors. […] Patients receiving benzodiazepines are more likely to have postoperative delirium than those who do not. […] The mechanisms responsible for postoperative cognitive changes are not fully understood, but it is certain that they are multifactorial.

• #20 Delirium in the ICU: an overview | Annals of Intensive Care | Full Text

  https://annalsofintensivecare.springeropen.com/articles/10.1186/2110-5820-2-49

  Another mechanism implicated in the pathophysiology of delirium is overactivity of the dopaminergic system. […] Both increased serotonergic activity and a relative serotonin deficiency also have been associated with delirium. […] Patients who are more prone to delirium, such as the elderly or those with underlying central nervous system disease, also may have heightened central nervous system response to inflammatory mediators. […] The amino-acid neurotransmitter system has a prominent role in the pathophysiology of alcohol withdrawal syndrome.

• #20 Delirium in the ICU: an overview | Annals of Intensive Care | Full Text

  https://annalsofintensivecare.springeropen.com/articles/10.1186/2110-5820-2-49

  Delirium is characterized by a disturbance of consciousness with accompanying change in cognition. […] Physiologically, delirium is characterized by a derangement of cerebral metabolism with cerebral dysfunction and is usually caused by a general medical illness, intoxication, or substance withdrawal. […] Different mechanisms have been proposed to explain the pathophysiology of delirium. However, these mechanisms are not mutually exclusive and it is likely that they often act in concert. One hypothesis postulates that decreased cholinergic activity may lead to delirium. […] Acetylcholine down regulates inflammation. Thus, it is not surprising that there is an imbalance between inflammatory and anti-inflammatory mediators in delirium, with increased levels of inflammatory mediators and a blunted anti-inflammatory response.

• #21 Delirium – Wikipedia

  https://en.wikipedia.org/wiki/Delirium

  The leading „neuroinflammatory hypothesis” (where neurodegenerative disease and aging leads the brain to respond to peripheral inflammation with an exaggerated CNS inflammatory response) has been described, but current evidence is still conflicting and fails to concretely support this hypothesis. […] Evidence for changes in structural and functional markers include: changes in white-matter integrity (white matter lesions), decreases in brain volume (likely as a result of tissue atrophy), abnormal functional connectivity of brain regions responsible for normal processing of executive function, sensory processing, attention, emotional regulation, memory, and orientation, differences in autoregulation of the vascular vessels in the brain, reduction in cerebral blood flow and possible changes in brain metabolism (including cerebral tissue oxygenation and glucose hypometabolism).

• #22 Sepsis-Associated Delirium: A Narrative Review

  https://www.mdpi.com/2077-0383/12/4/1273

  Delirium is characterized by an acutely altered mental status accompanied by reductions in cognitive function and attention. […] The mechanisms underlying SAD currently remain unclear; however, neurological decline is observed in patients with chronic sepsis. SAD has been attributed to a combination of neuroinflammation and disturbances in brain perfusion, the blood–brain barrier, and neurotransmission. […] During sepsis, endothelial cells are activated by increased systemic levels of the proinflammatory cytokines IL-1β, IL-6, and TNF-α. Endothelial cell activation also promotes the production of reactive oxygen species. The blood–brain barrier is permeable to proinflammatory cytokines and reactive oxygen species, which may contribute to the development of SAD. […] Many factors are involved in SAD, and most of the underlying mechanisms proposed to date have been derived from the findings of animal studies or cell culture experiments. […] Therefore, sepsis causes diffuse brain damage, which may lead to the development of SAD.

• #23 Study protocol: understanding the pathophysiologic mechanisms underlying delirium in older people undergoing hip fracture surgery | BMC Geriatrics | Full Text

  https://bmcgeriatr.biomedcentral.com/articles/10.1186/s12877-021-02584-1

  Postoperative delirium (POD) is a common complication of older people undergoing hip fracture surgery, which negatively affects clinical- and healthcare-related outcomes. Unfortunately, POD pathophysiology is still largely unknown, despite previous studies showing that neuroinflammation, neuroendocrine dysfunction, increased reactive oxidative stress (ROS), and endothelial dysfunctions may be involved. […] The pathophysiology of POD remains largely unknown. However, an increasing body of evidence suggests that neuroinflammation and a damage of blood-brain barrier (BBB) are involved: endothelium lesions at the BBB level can result in an increased permeability, allowing immune cells, cytokines and other neuroinflammatory products to enter brain parenchyma. This mechanism is particularly likely to occur in old and demented subjects with hip fracture, as elevated serum levels of pro-inflammatory cytokines including tumour necrosis factor- (TNF-), interleukin-1 (IL-1), IL-6, and IL-8 have been reported in these patients.

• #24 The Neurobiology of Delirium in a Septic Elderly Hospitalized Patient – Mass General Advances in Motion

  https://advances.massgeneral.org/research-and-innovation/case-study.aspx?id=1039

  Next, the neuroinflammation hypothesis argues that systemic inflammation triggered by insults (e.g., trauma and sepsis) can activate the immune cells of the CNS (i.e., microglia, astrocytes) to release reactive oxygen species and other inflammatory mediators that can precipitate to neuronal injury. In situations where microglia and astrocytes have been „primed” by prior aging and neurodegeneration, they are likely to be even more reactive to peripheral cytokines leading to greater neuronal insult. The greater the insult, and the fewer the functional reserves at baseline, the more likely someone is to develop delirium. […] The third proposed etiology of delirium is related to disturbances in neurotransmitter balance. This imbalance may be induced by anticholinergic or GABAergic medications, impaired renal or hepatic clearance of such drugs, polypharmacy, or drug withdrawal. Finally, the fourth proposed mechanism, impaired network connectivity, suggests that our brain functions best with strong integration between different neural networks. Aging or other neurodegenerative pathologies break down those connections, making us more vulnerable to confusion when an outside insult, such as an anticholinergic medication, disrupts the balance.

• #25 Study protocol: understanding the pathophysiologic mechanisms underlying delirium in older people undergoing hip fracture surgery | BMC Geriatrics | Full Text

  https://bmcgeriatr.biomedcentral.com/articles/10.1186/s12877-021-02584-1

  After crossing BBB, inflammatory mediators can activate microglia, leading to synaptic and neuronal dysfunction, and, eventually, delirium. […] A second pathophysiological mechanism has been proposed to explain delirium, relying on the oxidative stress hypothesis. Under specific circumstances, such as during surgery, the brain is highly vulnerable to damage of oxidative stress, possibly leading to neuronal dysfunction. […] A third pathophysiological hypothesis proposes that delirium represents a response to acute or chronic stress, mediated by abnormally high glucocorticoid (GC) levels. […] Previous studies have shown that patients who experience POD have higher postoperative cortisol levels with enhanced postoperative elevation in relation to baseline. […] All these hypotheses should not be considered as mutually exclusive pathophysiological mechanisms for delirium occurrence but, on the contrary, they should be regarded as complementary, with many areas of intersection and reciprocal influence.

• #26 Role of glia in delirium: proposed mechanisms and translational implications | Molecular Psychiatry

  https://www.nature.com/articles/s41380-024-02801-4

  Glial dysfunction has been described in delirium, but the underlying pathophysiological mechanisms are not fully understood. […] Reactive astrocytes with increased inflammasome activity, altered metabolism and impaired glymphatic activity have been reported in patients and models with delirium. […] Impaired blood-brain barrier function and white matter changes have also been noted. […] The glymphatic system represents a possible therapeutic target for delirium, especially post-operatively, but further studies are needed. […] Dysregulation of pro-inflammatory and pro-reparative signals from microglia, for example during neurodegeneration, result in neuronal dysfunction, cell death and synapse loss. […] The precise contribution of BBB impairment to delirium remains unclear and assessment of BBB integrity can provide widely varying results depending on the methodology used.

• #27 Role of glia in delirium: proposed mechanisms and translational implications | Molecular Psychiatry

  https://www.nature.com/articles/s41380-024-02801-4

  Delirium is associated with morbidity and mortality, causes distress to patients and carers, and has significant socioeconomic costs in ageing populations. […] Despite its clinical significance, the pathophysiology of delirium is understudied, and many underlying cellular mechanisms remain unknown. […] Although many studies focus on neuronal dysfunction in delirium, glial cells, primarily astrocytes, microglia, and oligodendrocytes, and their associated systems, are increasingly implicated in delirium pathophysiology. […] In particular, we focus on how astrocyte pathology, including aberrant brain energy metabolism and glymphatic dysfunction, reactive microglia, blood-brain barrier impairment, and white matter changes may contribute to the pathogenesis of delirium. […] Together, animal models suggest that cellular priming, defined as enhanced cellular reactivity on the background of pre-existing pathology, plays an important part in the pathogenesis of delirium.

• #28 NIDUS Delirium Bibliography

  https://deliriumnetwork.org/bibliography/?pdb=8461&listpage=65&instance=2

  Dexmedetomidine blocks cholinergic dysregulation in delirium pathogenesis in patients with major surgery […] Pathogenesis of postoperative delirium (POD) includes cholinergic dysfunction and deregulated inflammatory response to surgical trauma. […] From these data it can be assumed that dexmedetomidine could alleviate POD via altering the cholinergic anti-inflammatory pathway (CAIP).

• #29 Delirium – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK470399/

  Changes associated with age lead to diminished physiologic reserve and increased vulnerability to physical stress and illness. Some changes associated with age include decreased brain blood perfusion, increased neuron loss, and changes in the proportion of stress-regulating neurotransmitters. […] Peripheral inflammatory insults damage endothelial cell-cell adhesions at the blood-brain barrier. The increased endothelial permeability promotes inflammation in the central nervous system, causing further damage, ischemia, and neuronal death. […] Reactive oxygen species and reactive nitrogen species are mediators of cellular damage. The central nervous system is particularly vulnerable to reactive oxygen species due to its high lipid content and low antioxidant capacity. […] Disruption in sleep duration and architecture and melatonin secretion leads to dysfunction of many systems. Melatonin affects many functions in the central nervous system, including regulation of sleep-wake cycles, glucose regulation, core body temperature, antioxidant defenses, and immune system response.

• #30 Delirium: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/288890-overview

  Studies have suggested a role for cytokines, such as interleukin-1 and interleukin-6, in the pathogenesis of delirium. […] Studies indicate psychosocial stress and sleep deprivation facilitate the onset of delirium. […] The specific neuronal pathways that cause delirium are unknown. Imaging studies of metabolic (eg, hepatic encephalopathy) and structural (eg, traumatic brain injury, stroke) factors support the hypothesis that certain anatomical pathways may play a more important role than others. […] Disrupted bloodbrain barrier can allow neurotoxic agents and inflammatory cytokines to enter the brain and may cause delirium.

• #31

  https://link.springer.com/article/10.1007/s00134-018-5276-8

  If microglia is already primed by preceding events or concurrent neurodegenerative processes, its overactivation leads to BBB disruption with further brain penetration of pro-inflammatory cytokines and fluid shift with brain edema that alter synaptic transmission and neural excitability, impair microcirculation and favor uncoupling of oxidative phosphorylation with reduced neuronal energy production and ischemia. […] Reduced cholinergic activity (and, hence, reduced inhibition of microglia activity), increased release of norepinephrine, glutamate and dopamine, as well as the imbalance of other neurotransmitters create a vicious cycle of neuroinflammation, neurotransmitter imbalance and ischemic damage leading to neuronal death, severe prolonged delirium and long term cognitive impairment.

• #32 Role of glia in delirium: proposed mechanisms and translational implications | Molecular Psychiatry

  https://www.nature.com/articles/s41380-024-02801-4

  BBB permeability, measured by the CSF:plasma albumin ratio, correlates with post-operative delirium incidence, severity, and delayed recovery. […] Astrocytes mediate signalling between neurons and the vasculature and increase CBF in response to neuronal activity. […] The impaired crosstalk between glial cells in delirium also warrants further investigation.

• #33

• #34 Delirium: Clinical Manifestation and Management In The Emergency Department | RECAPEM

  https://recapem.com/delirium-clinical-manifestation-and-management-in-the-emergency-department/

  Several studies support the cholinergic hypothesis of delirium. […] Medical conditions precipitating delirium, such as hypoxia, hypoglycemia, and thiamine deficiency, decrease acetylcholine synthesis in the CNS. […] GABAergic activity has been implicated in hepatic encephalopathy (HE). […] Dopaminergic activity has been implicated in causing delirium associated with bupropion toxicity. […] Cerebral metabolic insufficiency: The brain requires a large amount of energy, as either oxygen or glucose deficiency can markedly constrain brain function. […] Systemic inflammation is a well-established trigger of delirium, but the precise mechanisms by which it disrupts brain function are not clearly understood. […] Impaired neuronal network connectivity: Neurochemical influences on the brain’s functional state are dependent on the neuroanatomical networks in which these neurotransmitters operate. […] Structural connectivity studies show that loss of integrity in the inter-hemispheric corpus callosum is associated with increased delirium duration.

• #35 Intranasal insulin for treatment of delirium in older hospitalised patients: study protocol for a randomised controlled trial | BMJ Open

  https://bmjopen.bmj.com/content/11/10/e050765

  Delirium pathophysiology is poorly understood, although several hypotheses exist. These include neuroinflammation, neurotransmitter dysregulation, neuroendocrine dysregulation and neural network dysconnectivity. […] Research has identified altered cerebral perfusion and metabolism as a feature of delirium. Delirious patients have higher cerebrospinal fluid lactate and lower neuron-specific enolase suggesting suppressed aerobic metabolism during an episode of delirium. […] It is now well established that the brain is an insulin sensitive organ; insulin receptors are widely expressed in the brain, with greatest saturation in the corticolimbic structures. Insulin enhances learning and memory by modulating neuronal growth, metabolism, plasticity and cholinergic function. […] The role of glucose metabolism in the pathogenesis of neurodegenerative disease is a growing area of research. Mild Cognitive Impairment (MCI) and Alzheimers dementia (AD) have been characterised as states of brain-specific insulin resistance and deficiency sometimes called type 3 diabetes.

• #36

  https://scitemed.com/article/2687/Epidemiology,-Mechanisms,-Diagnosis,-and-Treatment-of-Delirium-A-Narrative-Review

  Associated factors include decreased oxidative metabolism secondary to atherosclerosis and ischemia, although studies examining the relation of white matter hyperintensities to delirium have produced conflicting results. […] Changes in the microarchitecture of the brain secondary to aging, with gradual accumulation of damage to neurons and astrocytes have also been postulated.

• #37 Unravelling the pathophysiology of delirium: a focus on the role of aberrant stress responses

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4311661/

  We suggest that it is heuristically useful to class over-stimulation of stress responses, or pathological reaction of target tissues to stressors, as a second major category of mechanisms of delirium. […] This separate class of pathways to delirium is here given the general label of aberrant stress responses. […] We will focus on two major types of aberrant stress responses which can lead to attentional deficits and other forms of acute mental status change: exaggerated cytokine-induced sickness behaviour, and limbic hypothalamic-pituitary-adrenal (LHPA) axis dysfunction. […] Another hypothesis of delirium pathophysiology is that pathologically sustained high levels of cortisol occurring with acute stress can precipitate and/or sustain delirium. […] In summary, a role for dysfunction of the LHPA in delirium is suggested by two lines of evidence: (a) sustained high cortisol levels occur in some older people, particularly those with cognitive impairment following stress, and (b) sustained high cortisol levels are known to cause cognitive impairment and other neuropsychiatric deficits, particularly in older adults. […] In conclusion, there is some evidence that dysregulation of the LHPA axis plays a role in delirium, though definitive data are still lacking.

• #38 Intranasal insulin for treatment of delirium in older hospitalised patients: study protocol for a randomised controlled trial | BMJ Open

  https://bmjopen.bmj.com/content/11/10/e050765

  Given that intranasal insulin improves cognition as well as cerebral perfusion and metabolism, this trial will investigate its potential role in treatment of delirium. […] Although the pathophysiological mechanisms are incompletely understood, it is probable that an episode of delirium causes irreversible neuronal damage leading to sustained cognitive and functional impairment, with prolonged delirium exposure leading to greater cerebral damage. […] To date, there are no trials assessing intranasal insulin as a treatment for delirium, however, it could improve cognitive and clinical outcomes for delirious patients via a variety of mechanisms. Intranasal insulin increases cerebral perfusion and increases or maintains cerebral glucose metabolism on FDG-PET. […] The hypothalamic-pituitary-adrenal (HPA) axis is also insulin responsive and following administration of intranasal insulin healthy populations demonstrate diminished saliva and plasma cortisol. As aberrant HPA axis activity is hypothesised to contribute to delirium pathophysiology, modification of this pathway may also lead to improved outcomes.

• #39

  https://www.nursingcenter.com/lnc/ce_articleprint?an=00129191-201308000-00005

  Alterations in the sleep/wake cycle have long been associated with delirium. The delirious state is known to include symptoms of daytime somnolence and reversal of the sleep/wake cycle as well as sleep interrupted by agitation and restlessness. It remains uncertain whether a disrupted sleep cycle is a cause or consequence of delirium. A recent prospective, longitudinal study of 105 hospice patients found that poor sleep quality precedes delirium onset, adding support to a causal relationship between sleep disturbance and delirium. […] The overarching theme reported by caregivers of delirious patients in this study was suffering. Clinicians share an understanding that delirium involves sufferable states, including pain, which are challenging to define. In the current study, participants stated both indirectly and directly that they also experienced suffering as they witnessed the loss of personhood, which characterizes delirium. Suffering was also associated with each of the other categories of delirium-associated changes as well. There is an element of suffering associated with physical and cognitive decline, as well as patient withdrawal from loved ones, activities, and interests. Given complications such as nocturnal agitation and sleeplessness, it is not surprising that the interviews conducted in this study suggested that deteriorating sleep plays a key role in contributing to overall suffering for both patients and their caregivers.

• #40 Thieme E-Journals – Seminars in Neurology / Abstract

  https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0044-1791666

  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. […] To develop therapies to shorten the duration and limit the adverse effects of delirium, it is important to understand the mechanisms underlying its presentation. 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. […] 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.

• #41 Delirium – Wikipedia

  https://en.wikipedia.org/wiki/Delirium

  Since the 1950s, delirium has been known to be associated with slowing of resting-state EEG rhythms, with abnormally decreased background alpha power and increased theta and delta frequency activity. […] From such evidence, a 2018 systematic review proposed a conceptual model that delirium results when insults/stressors trigger a breakdown of brain network dynamics in individuals with low brain resilience (i.e. people who already have underlying problems of low neural connectivity and/or low neuroplasticity like those with Alzheimer’s disease). […] Only a handful of studies exist where there has been an attempt to correlate delirium with pathological findings at autopsy. […] A case-control study showed that 9 delirium cases showed higher expression of HLA-DR and CD68 (markers of microglial activation), IL-6 (cytokines pro-inflammatory and anti-inflammatory activities) and GFAP (marker of astrocyte activity) than age-matched controls; this supports a neuroinflammatory cause to delirium, but the conclusions are limited by methodological issues.

• #42 Pathogenesis of Delirium

  https://ouci.dntb.gov.ua/en/works/4Nn0DO64/

  Pathogenesis of Delirium […] The neuroinflammatory hypothesis of delirium. […] Pathoetiological model of delirium: comprehensive understanding of the neurobiology of delirium and an evidence-based approach to prevention and treatment. […] The neuropathogenesis of delirium: a need to focus our research. […] The role of genetics in delirium in the elderly patient. […] The neuropathogenesis of delirium.

• #43 Delirium – Psychiatry – Diseases – McMaster Textbook of Internal Medicine

  https://empendium.com/mcmtextbook/chapter/B31.II.21.21.

  Delirium is an acute clinical syndrome characterized by fluctuating confusion, inattention, disorganized thinking, and altered levels of consciousness. […] The pathophysiology of delirium is poorly understood. There are several proposed hypotheses, but accumulating evidence suggests that there are likely multiple interacting factors disrupting normal neuronal brain function. Delirium appears to be the final common pathway and expression of multiple different pathologies that disrupt multiple brain regions and neurotransmitter systems. These include, but are not limited to, altered neurotransmission due to cholinergic deficiency and/or dopamine excess, stress-induced inflammation and cytokine release, cerebral hypoxia, disturbances in tryptophan metabolism, chronic physiological stress (eg, hypercortisolism) and genetic factors (eg, apolipoprotein E genotype variance leading to disturbance of normal physiological processes). Different mechanisms may be more prominent depending on the circumstance (eg, postoperative, ICU, general medical illness).

• #44 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20210217/New-study-sheds-light-on-potential-pathophysiological-mechanism-underlying-delirium.aspx

  The researchers’ analysis of more than 1,300 proteins revealed a single protein (known as chitinase-3-like-protein-1, or CHI3L1/YKL-40) that was present at higher concentrations in the blood both before and after surgery in patients who experienced delirium as compared with patients who did not develop postoperative delirium. […] „Our study specifically highlights the involvement of this highly specific immune activating protein in postoperative delirium, which may also play a role in COVID-19 associated delirium,” said Libermann, who is also an Associate Professor of Medicine at Harvard Medical School. „In addition to providing a promising candidate for a delirium biomarker, our findings suggest a possible link between delirium, aging and Alzheimer’s disease.”

• #45 Delirium tremens pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Delirium_tremens_pathophysiology

  Delirium tremens is the most severe form of alcohol withdrawal syndrome. The effects of alcohol on the brain and neurological system are depressant. When alcohol is abruptly removed after a period of chronic use, the brain and nervous system struggle to recalibrate, resulting in brain overstimulation. […] It is understood that delirium tremens result from altering the activity of GABA, chloride ion, and NMDA receptors in the brain due to prolonged alcohol exposure. Abrupt cessation of alcohol causes overstimulation in these receptors. […] Delirium tremens appears after a rapid reduction in the amount of alcohol being consumed by heavy drinkers, or a rapid reduction of intake of benzodiazepines or barbiturates. If caused by alcohol, it only occurs in individuals with a history of constant, long-term alcohol consumption.

• #46 Delirium Tremens (DTs): Practice Essentials, Pathophysiology, Etiology of Delirium Tremens

  https://emedicine.medscape.com/article/166032-overview

  Chronic intake of alcohol affects several neurotransmitter systems in the brain. These effects include (1) increased release of endogenous opiates; (2) activation of the inhibitory gamma-aminobutyric acid-A (GABA-A) receptor producing increased GABA inhibition, with a resultant influx of chloride ions; (3) up-regulation of the postsynaptic N-methyl-D-aspartate (NMDA) type of glutamate receptor, which mediates the postsynaptic excitatory effects of glutamate; and (4) interactions with serotonin and dopamine receptors. […] During withdrawal from alcohol, the loss of GABA-A receptor stimulation causes a reduction in chloride flux and is associated with tremors, diaphoresis, tachycardia, anxiety, and seizures. In addition, the lack of inhibition of the NMDA receptors may lead to seizures and delirium. Excessive nervous system excitability during periods of abstinence from alcohol is related to the effect of alcohol on the number and function of brain receptors.

• #47 Delirium tremens pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Delirium_tremens_pathophysiology

  The exact pharmacology of ethanol is not fully understood: however, it is theorized that delirium tremens is caused by the effect of alcohol on the benzodiazepine-GABAA-chloride receptor complex for the inhibitory neurotransmitter GABA. […] This causes downregulation of these receptors, as well as an up-regulation in the production of excitatory neurotransmitters such as norepinephrine, dopamine, epinephrine, and serotonin – all of which further the drinker’s tolerance to alcohol and may intensify tonic-clonic seizures. […] When alcohol is no longer consumed, these down-regulated GABAA receptor complexes are so insensitive to GABA that the typical amount of GABA produced has little effect; compounded with the fact that GABA normally inhibits action potential formation, there are not as many receptors for GABA to bind to – meaning that sympathetic activation is unopposed. This is also known as an „adrenergic storm”.

• #48 Delirium tremens pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Delirium_tremens_pathophysiology

  Effects of this „adrenergic storm” can include (but are not limited to) tachycardia, hypertension, hyperthermia, hyperreflexia, diaphoresis, heart attack, cardiac arrhythmia, stroke, anxiety, panic attacks, paranoia, and agitation. […] This is all made worse by excitatory neurotransmitter upregulation, so not only is sympathetic nervous system over-activity unopposed by GABA, there is also more of the serotonin, norepinephrine, dopamine, epinephrine, and particularly glutamate. Excitory NMDA receptors are also upregulated, contributing to the delirium and neurotoxicity (by excitotoxicity) of withdrawal. […] Direct measurements of central norepinephrine and its metabolites is in direct correlation to the severity of the alcohol withdrawal syndrome.

• #49 What drives post-surgical delirium risk among older patients | American Medical Association

  https://www.ama-assn.org/delivering-care/population-care/what-drives-post-surgical-delirium-risk-among-older-patients

  Trauma-induced inflammation appears to be the underlying mechanism of post-operative delirium, said Dr. Vacas during her presentation at the 2022 AMA Annual Meeting. […] Following trauma, such as a surgery, the bone marrow-derived macrophages cross the disruptive blood-brain barrier and reach the brain, where they can damage the hippocampus and interfere with processes responsible for learning and memory, she said.

• #50 Delirium in Severe Acute Respiratory Syndrome-Coronavirus-2 Infection: A Point of View

  https://www.heraldopenaccess.us/openaccess/delirium-in-severe-acute-respiratory-syndrome-coronavirus-2-infection-a-point-of-view

  Delirium, a serious disturbance in mental abilities, encompasses an organic-based decline from a preceding baseline mental status, develops over a short period of time, and includes disturbances in cognition, attention, consciousness, and perceptual disturbances (such as delusions and/or hallucinations). […] New and emerging evidence suggest that delirium onset and/or development in the context of SARS-CoV-2 infection is possibly due to multiple factors, including (1) hypoxia and oxygen deficiency of the brain, (2) neuronal inflammation due to cytokine storm as a result of a strong activation of the immune system, and/or (3) direct CNS invasion and neuronal toxicity. […] Hypoxia, a condition in which the body and/or a region of the body, such as the brain, is deprived of oxygen at the tissue level, can result in neuronal swelling and brain edema which can lead to neurological and brain damages.

• #51 Delirium in Severe Acute Respiratory Syndrome-Coronavirus-2 Infection: A Point of View

  https://www.heraldopenaccess.us/openaccess/delirium-in-severe-acute-respiratory-syndrome-coronavirus-2-infection-a-point-of-view

  Brain immune mediated injury, on the other hand, is due to the cytokine storms, a fact that increases the levels of inflammatory cytokines and activation of T lymphocytes, macrophages, and endothelial cells, causing a release of Interleukins 6 (IL6), vascular leakage, activation of complement and coagulation cascade, and disseminated intravascular coagulation, finally producing brain damage. […] Finally, and although direct CNS invasion and neuronal toxicity is not by far common (as compared to other manifestations) there is a well-established pathological evidence of past CoVs directly affecting the CNS. […] Different teams have already shown with data coming from animal and clinical studies that CoVs are able to cross the blood-brain barrier (BBB) and penetrate into the CNS, causing neuronal invasion, and four different transmission routes for SARS-CoV-2 neuronal CNS invasion have been suggested.

• #52 Delirium in Severe Acute Respiratory Syndrome-Coronavirus-2 Infection: A Point of View

  https://www.heraldopenaccess.us/openaccess/delirium-in-severe-acute-respiratory-syndrome-coronavirus-2-infection-a-point-of-view

  Even if research is extensive, and delirium is mainly characterized as being caused by systemic inflammatory condition, the actual mechanism of delirium is not clearly delineated. […] Delirium, cognitive deficits and behavioural abnormalities in the context of COVID-19 are possibly caused by systemic inflammation and conditions of prolonged hypoxia, inducing the long-lasting and non-controlled neuronal inflammation cascade damaging areas such as the hippocampus and/or other cortical areas associated with the cognitive dysfunctions and the behavioural alterations presented by patients suffering delirium. […] If SARS-CoV-2 binding to brain ACE2 receptors, with the consequent membrane fusion and virus entry into the cell, could lead to down-regulation of these receptors, in line with different authors and groups, with subsequent inflammatory lesions at the brain level, or different neurotransmitter imbalances, is a question to be resolved.

• #53 The Biochemical Basis of Delirium | Springer Nature Experiments

  https://experiments.springernature.com/articles/10.1007/978-1-4939-9891-3_14

  Delirium is an important clinical diagnosis that is common in the post-operative period and in critically ill patients. It is associated with an increase in morbidity, mortality and resource utilization. […] Though the pathogenesis of delirium has been increasingly recognized for its importance and has been an intensively studied in recent years, the biochemical mechanism for its development is still debated. This review scrutinized a number of studies in order to better characterize the biochemical basis for delirium, with particular focus paid to the interactions of the cholinergic system, the cholinergic anti-inflammatory pathway, the immune system and neuroinflammation. […] As the biochemical basis of delirium becomes more clearly defined, future research into therapeutics based on immune modulation and treatment of neuroinflammation may prove to be very promising.

• #54 Thieme E-Journals – Seminars in Neurology / Abstract

  https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0044-1791666

  Emerging animal models that can mimic delirium-like clinical states will reveal further insights into delirium pathophysiology. The combination of clinical and basic science methods of exploring delirium shows great promise in elucidating its underlying mechanisms and revealing potential therapeutic targets.

• #55 Delirium in older adults: Diagnosis, prevention, and treatment | British Columbia Medical Journal

  https://bcmj.org/articles/delirium-older-adults-diagnosis-prevention-and-treatment

  The pathophysiological changes described here also suggest that delirium itself can cause permanent neuronal damage, thereby contributing to the risk of cognitive decline. […] Given the cholinergic deficit theory in the pathogenesis of delirium, there have also been trials with acetylcholinesterase inhibitors, medications that increase the amount of acetylcholine in the synapse.

• #56 Assessment of delirium – Differential diagnosis of symptoms | BMJ Best Practice

  https://bestpractice.bmj.com/topics/en-gb/241

  The pathophysiology of delirium remains relatively unclear. In general, neuroimaging studies reveal disruptions in higher cortical functioning in multiple disparate areas of the brain, including the prefrontal cortex, subcortical structures, thalamus, basal ganglia, lingual gyri, and frontal, fusiform, and temporoparietal cortex. […] Theories on the pathogenesis of delirium point to the role of neurotransmitters, inflammation, and chronic stress on the brain. For example, the role of cholinergic deficiency in inducing delirium is strengthened by the clear association of anticholinergic drug use with increased incidence. […] Dopaminergic excess is also believed to contribute. Evidence does not appear to support the use of antipsychotic medications (dopamine antagonists) for the prevention or treatment of delirium, but is not entirely consistent.

• #57 Assessing and Managing Delirium in Older Adults

  https://www.aliem.com/delirium-in-older-adults/

  Older adults experience a phenomenon termed homeostenosis in which their physiologic reserve and the degree to which they can compensate for stressors is narrowed, putting them at risk for delirium. […] Underlying dementia is one of the most important risk factors for development of delirium, so the 2 impairments are often present simultaneously during a visit to the ED. […] Delirium serves both as a marker of brain vulnerability with decreased reserve and as a potential mechanism for permanent cognitive damage Inouye et al.

• #58 The Neurobiology of Delirium in a Septic Elderly Hospitalized Patient – Mass General Advances in Motion

  https://advances.massgeneral.org/research-and-innovation/case-study.aspx?id=1039

  The Pathways Service in the Department of Medicine at Massachusetts General Hospital was consulted and focused on elucidating the pathophysiology of this patient’s delirium, driven by two questions: […] Given that delirium is a complex, multifactorial phenomenon, it is thought that there are multiple different neurobiological mechanisms (or endotypes) that can lead to the clinical phenotype of delirium. In other words, delirium may be a spectrum of diseases with unique mechanisms. There are four different potential mechanisms proposed for delirium: bioenergetic insufficiency, neuroinflammation, neurotransmitter imbalance, and impaired network connectivity. The first proposed mechanism, bioenergetic insufficiency, posits that a lack of adequate glucose or oxygen or metabolic derangements (i.e., hyponatremia, uremia) diffusely in the central nervous system (CNS) can precipitate delirium, particularly in patients with premorbid factors such as advanced age and Alzheimer’s disease. Neurons are essentially starved for key nutrients beyond their capacity to function, leading to diffuse dysfunction.

• #59 Diagnosing and Treating Delirium in the ICU | Respiratory Exchange | Cleveland Clinic

  https://my.clevelandclinic.org/podcasts/respiratory-exchange/diagnosing-and-treating-delirium-in-the-icu

  We’ve also had studies evaluating neurotransmitters, so things like dopamine and serotonin and trying to distinguish whether there’s alterations in those bubbles, which has lead us to study certain medications in this disease state, because we are trying to work on altering the neuromodulation that we believe is occurring the state of delirium. […] I think ultimately, we need a better understanding of delirium pathophysiology and its association with long-term cognitive impairment. […] We have some leads with neurotransmitter modulation, inflammatory markers being elevated, but I think we still truly don’t know some of the true etiology and pathophysiology of delirium and it’d be important for us to be able to, one, better prevent delirium if we had more understanding in this area, and two, potentially look at medications that might be better equipped to manage delirium if we can better understand the pathophysiology.

• #60 Towards an understanding of the biological mechanisms of delirium using functional MRI: Pilot Study | British Geriatrics Society

  https://www.bgs.org.uk/towards-an-understanding-of-the-biological-mechanisms-of-delirium-using-functional-mri-pilot-study

  Delirium is a common condition in older hospitalised patients causing high morbidity and mortality. […] Several recent studies have demonstrated that functional neuroimaging in delirium is achievable and has suggested that a brain region termed the default mode network (DMN), may play a cardinal role in delirium pathogenesis. […] Preliminary fMRI analyses show a variable pattern of cortical recruitment during task engagement in delirious patients.

• #61

  https://actaorthop.org/actao/article/view/19569

  Postoperative delirium is a frequent and serious complication in elderly patients following operation for hip fracture, leading to an increased risk of complications. The pathophysiological mechanisms are unresolved, but probably multifactorial. […] The pathophysiology leading to delirium after hip fracture surgery still remains to be clarified and no single drug or surgical regimen has proven to be preventive. This calls for more detailed investigations of the differential role of different pathogenic mechanisms, as well as an aggressive multimodal approach to enhance recovery and reduce morbidity, as has proven to be successful in a variety of elective surgical procedures.

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