Neuropathogenesis of delirium: review of current etiologic theories and common pathways.
TL;DR: It is unlikely that any one of these theories is fully capable of explaining the etiology or phenomenologic manifestations of delirium but rather that two or more of these act together to lead to the biochemical derangement and, ultimately, to the complex cognitive and behavioral changes characteristic ofdelirium.
Abstract: Delirium is a neurobehavioral syndrome caused by dysregulation of neuronal activity secondary to systemic disturbances. Over time, a number of theories have been proposed in an attempt to explain the processes leading to the development of delirium. Each proposed theory has focused on a specific mechanism or pathologic process (e.g., dopamine excess or acetylcholine deficiency theories), observational and experiential evidence (e.g., sleep deprivation, aging), or empirical data (e.g., specific pharmacologic agents' association with postoperative delirium, intraoperative hypoxia). This article represents a review of published literature and summarizes the top seven proposed theories and their interrelation. This review includes the "neuroinflammatory," "neuronal aging," "oxidative stress," "neurotransmitter deficiency," "neuroendocrine," "diurnal dysregulation," and "network disconnectivity" hypotheses. Most of these theories are complementary, rather than competing, with many areas of intersection and reciprocal influence. The literature suggests that many factors or mechanisms included in these theories lead to a final common outcome associated with an alteration in neurotransmitter synthesis, function, and/or availability that mediates the complex behavioral and cognitive changes observed in delirium. In general, the most commonly described neurotransmitter changes associated with delirium include deficiencies in acetylcholine and/or melatonin availability; excess in dopamine, norepinephrine, and/or glutamate release; and variable alterations (e.g., either a decreased or increased activity, depending on delirium presentation and cause) in serotonin, histamine, and/or γ-aminobutyric acid. In the end, it is unlikely that any one of these theories is fully capable of explaining the etiology or phenomenologic manifestations of delirium but rather that two or more of these, if not all, act together to lead to the biochemical derangement and, ultimately, to the complex cognitive and behavioral changes characteristic of delirium.
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TL;DR: In this paper, the authors present consensus recommendations for the optimal perioperative management of patients undergoing cardiac surgery based on a review of meta-analyses, randomized clinical trials, large nonrandomized studies, and reviews.
Abstract: Enhanced Recovery After Surgery (ERAS) evidence-based protocols for perioperative care can lead to improvements in clinical outcomes and cost savings. This article aims to present consensus recommendations for the optimal perioperative management of patients undergoing cardiac surgery. A review of meta-analyses, randomized clinical trials, large nonrandomized studies, and reviews was conducted for each protocol element. The quality of the evidence was graded and used to form consensus recommendations for each topic. Development of these recommendations was endorsed by the Enhanced Recovery After Surgery Society.
513 citations
TL;DR: Both conventional and atypical antipsychotics and non-pharmacological interventions were shown to be important in the management of delirium, and more research is necessary to clarify how to more thoroughly manageDelirium in palliative care.
Abstract: Delirium is a complex but common disorder in palliative care with a prevalence between 13 and 88 % but a particular frequency at the end of life (terminal delirium). By reviewing the most relevant studies (MEDLINE, EMBASE, PsycLit, PsycInfo, Cochrane Library), a correct assessment to make the diagnosis (e.g., DSM-5, delirium assessment tools), the identification of the possible etiological factors, and the application of multicomponent and integrated interventions were reported as the correct steps to effectively manage delirium in palliative care. In terms of medications, both conventional (e.g., haloperidol) and atypical antipsychotics (e.g., olanzapine, risperidone, quetiapine, aripiprazole) were shown to be equally effective in the treatment of delirium. No recommendation was possible in palliative care regarding the use of other drugs (e.g., α-2 receptors agonists, psychostimulants, cholinesterase inhibitors, melatonergic drugs). Non-pharmacological interventions (e.g., behavioral and educational) were also shown to be important in the management of delirium. More research is necessary to clarify how to more thoroughly manage delirium in palliative care.
269 citations
TL;DR: Delirium is the most common neuropsychiatric syndrome encountered by clinicians dealing with older adults and the medically ill and is best characterized by 5 core domains: cognitive deficits, attentional deficits, circadian rhythm dysregulation, emotional Dysregulation, and alteration in psychomotor functioning.
Abstract: Background Delirium is the most common neuropsychiatric syndrome encountered by clinicians dealing with older adults and the medically ill and is best characterized by 5 core domains: cognitive deficits, attentional deficits, circadian rhythm dysregulation, emotional dysregulation, and alteration in psychomotor functioning. Design An extensive literature review and consolidation of published data into a novel interpretation of known pathophysiological causes of delirium. Results Available data suggest that numerous pathological factors may serve as precipitants for delirium, each having differential effects depending on patient-specific patient physiological characteristics (substrate). On the basis of an extensive literature search, a newly proposed theory, the systems integration failure hypothesis, was developed to bring together the most salient previously described theories, by describing the various contributions from each into a complex web of pathways-highlighting areas of intersection and commonalities and explaining how the variable contribution of these may lead to the development of various cognitive and behavioral dysfunctions characteristic of delirium. The specific cognitive and behavioral manifestations of the specific delirium picture result from a combination of neurotransmitter function and availability, variability in integration and processing of sensory information, motor responses to both external and internal cues, and the degree of breakdown in neuronal network connectivity, hence the term acute brain failure. Conclusions The systems integration failure hypothesis attempts to explain how the various proposed delirium pathophysiologic theories interact with each other, causing various clinically observed delirium phenotypes. A better understanding of the underlying pathophysiology of delirium may eventually assist in designing better prevention and management approaches.
265 citations
Cites background from "Neuropathogenesis of delirium: revi..."
...• Increase in baseline levels of circulating inflammatory mediators including Source: Modified from Maldonado.26 During various disease states (eg, inflammation), leukocytes adhere to the BBB endothelial cells, leading to disruption of cell‐cell adhesions and increased endothelial permeability, decreased perfusion and longer diffusion distance for oxygen,30,42 and enhanced infiltration of leukocytes and transport of cytokines into the CNS, producing ischemia and neuronal apoptosis.36,43 Studies have suggested that various anesthetic agents (eg, sevoflurane and isoflurane) can cause marked disruption of BBB‐associated tight junctions, leading to increased BBB permeability (Figure 8).44,45 The frequency and magnitude of this effect increase with age, thus potentially serving as a mechanism to mediate POD....
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...A relationship between dexamethasone nonsuppression and various neuropathological states has been described in dementia91-93 and delirium.83,94-96 Those at higher risk for delirium (eg, older adults with baseline cognitive impairment) exhibited sustained high cortisol levels after major stressors likely due to impaired feedback regulation of the LHPA axis.78,96-99 Cortisol nonsuppression after dexamethasone administration has been associated with delirium in 78% of subjects Source: Modified from Maldonado.26 experiencing lower respiratory tract infection.83 Among postoperative100 and poststroke95,101 patients, increased cortisol levels and/or HPA axis dysregulation has been associated with the development of delirium....
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...2 | Inflammation: neuroinflammatory hypothesis According to the neuroinflammatory hypothesis (NIH), delirium represents the central nervous system (CNS) manifestation of a systemic disease state that has crossed the blood‐brain barrier (BBB).(26,27)...
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...• Increase in baseline levels of circulating inflammatory mediators including Source: Modified from Maldonado.(26) During various disease states (eg, inflammation), leukocytes adhere to the BBB endothelial cells, leading to disruption of cell‐cell adhesions and increased endothelial permeability, decreased perfusion and longer diffusion distance for oxygen,(30,42) and enhanced infiltration of leukocytes and transport of cytokines into the CNS, producing ischemia and neuronal apoptosis....
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...The mechanisms linking excess GC release and neuronal injury and/or exacerbate cell death have been described elsewhere (Table 5).(26) The loss of normal inhibition of adrenal steroidogenesis results in continuous secretion of peak amounts of corticosteroids....
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TL;DR: The frequency of delirium in critically ill children, its duration, associated risk factors, and effect on in-hospital outcomes, including mortality are described, with a strong and independent predictor of mortality.
Abstract: Objectives:Delirium occurs frequently in adults and is an independent predictor of mortality. However, the epidemiology and outcomes of pediatric delirium are not well-characterized. The primary objectives of this study were to describe the frequency of delirium in critically ill children, its durat
237 citations
Cites background from "Neuropathogenesis of delirium: revi..."
...It is likely that although the final common pathway leading to delirium may be the same (alteration in neurotransmission, which results in an acute and fluctuating change in awareness and cognition), there are many disparate etiologies that can trigger the delirium cascade(43)....
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TL;DR: In patients receiving palliative care, individualized management ofdelirium precipitants and supportive strategies result in lower scores and shorter duration of target distressing delirium symptoms than when risperidone or haloperidol are added.
Abstract: Importance Antipsychotics are widely used for distressing symptoms of delirium, but efficacy has not been established in placebo-controlled trials in palliative care. Objective To determine efficacy of risperidone or haloperidol relative to placebo in relieving target symptoms of delirium associated with distress among patients receiving palliative care. Design, Setting, and Participants A double-blind, parallel-arm, dose-titrated randomized clinical trial was conducted at 11 Australian inpatient hospice or hospital palliative care services between August 13, 2008, and April 2, 2014, among participants with life-limiting illness, delirium, and a delirium symptoms score (sum of Nursing Delirium Screening Scale behavioral, communication, and perceptual items) of 1 or more. Interventions Age-adjusted titrated doses of oral risperidone, haloperidol, or placebo solution were administered every 12 hours for 72 hours, based on symptoms of delirium. Patients also received supportive care, individualized treatment of delirium precipitants, and subcutaneous midazolam hydrochloride as required for severe distress or safety. Main Outcome and Measures Improvement in mean group difference of delirium symptom score (severity range, 0-6) between baseline and day 3. Five a priori secondary outcomes: delirium severity, midazolam use, extrapyramidal effects, sedation, and survival. Results Two hundred forty-seven participants (mean [SD] age, 74.9 [9.8] years; 85 women [34.4%]; 218 with cancer [88.3%]) were included in intention-to-treat analysis (82 receiving risperidone, 81 receiving haloperidol, and 84 receiving placebo). In the primary intention-to-treat analysis, participants in the risperidone arm had delirium symptom scores that were significantly higher than those among participants in the placebo arm (on average 0.48 Units higher; 95% CI, 0.09-0.86;P = .02) at study end. Similarly, for those in the haloperidol arm, delirium symptom scores were on average 0.24 Units higher (95% CI, 0.06-0.42;P = .009) than in the placebo arm. Compared with placebo, patients in both active arms had more extrapyramidal effects (risperidone, 0.73; 95% CI, 0.09-1.37;P = .03; and haloperidol, 0.79; 95% CI, 0.17-1.41;P = .01). Participants in the placebo group had better overall survival than those receiving haloperidol (hazard ratio, 1.73; 95% CI, 1.20-2.50;P = .003), but this was not significant for placebo vs risperidone (hazard ratio, 1.29; 95% CI, 0.91-1.84;P = .14). Conclusions and Relevance In patients receiving palliative care, individualized management of delirium precipitants and supportive strategies result in lower scores and shorter duration of target distressing delirium symptoms than when risperidone or haloperidol are added. Trial Registration anzctr.org.au Identifier:ACTRN12607000562471.
227 citations
References
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11 Jun 2013
113,134 citations
TL;DR: In response to a peripheral infection, innate immune cells produce pro-inflammatory cytokines that act on the brain to cause sickness behaviour, which can lead to an exacerbation of sickness and the development of symptoms of depression in vulnerable individuals.
Abstract: In response to a peripheral infection, innate immune cells produce pro-inflammatory cytokines that act on the brain to cause sickness behaviour. When activation of the peripheral immune system continues unabated, such as during systemic infections, cancer or autoimmune diseases, the ensuing immune signalling to the brain can lead to an exacerbation of sickness and the development of symptoms of depression in vulnerable individuals. These phenomena might account for the increased prevalence of clinical depression in physically ill people. Inflammation is therefore an important biological event that might increase the risk of major depressive episodes, much like the more traditional psychosocial factors.
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TL;DR: Sleep debt has a harmful impact on carbohydrate metabolism and endocrine function similar to those seen in normal ageing and, therefore, sleep debt may increase the severity of age-related chronic disorders.
3,322 citations
TL;DR: Delirium was an independent predictor of higher 6-month mortality and longer hospital stay even after adjusting for relevant covariates including coma, sedatives, and analgesics in patients receiving mechanical ventilation.
Abstract: ContextIn the intensive care unit (ICU), delirium is a common yet underdiagnosed
form of organ dysfunction, and its contribution to patient outcomes is unclear.ObjectiveTo determine if delirium is an independent predictor of clinical outcomes,
including 6-month mortality and length of stay among ICU patients receiving
mechanical ventilation.Design, Setting, and ParticipantsProspective cohort study enrolling 275 consecutive mechanically ventilated
patients admitted to adult medical and coronary ICUs of a US university-based
medical center between February 2000 and May 2001. Patients were followed
up for development of delirium over 2158 ICU days using the Confusion Assessment
Method for the ICU and the Richmond Agitation-Sedation Scale.Main Outcome MeasuresPrimary outcomes included 6-month mortality, overall hospital length
of stay, and length of stay in the post-ICU period. Secondary outcomes were
ventilator-free days and cognitive impairment at hospital discharge.ResultsOf 275 patients, 51 (18.5%) had persistent coma and died in the hospital.
Among the remaining 224 patients, 183 (81.7%) developed delirium at some point
during the ICU stay. Baseline demographics including age, comorbidity scores,
dementia scores, activities of daily living, severity of illness, and admission
diagnoses were similar between those with and without delirium (P>.05 for all). Patients who developed delirium had higher 6-month
mortality rates (34% vs 15%, P = .03) and spent 10
days longer in the hospital than those who never developed delirium (P<.001). After adjusting for covariates (including age,
severity of illness, comorbid conditions, coma, and use of sedatives or analgesic
medications), delirium was independently associated with higher 6-month mortality
(adjusted hazard ratio [HR], 3.2; 95% confidence interval [CI], 1.4-7.7; P = .008), and longer hospital stay (adjusted HR, 2.0;
95% CI, 1.4-3.0; P<.001). Delirium in the ICU
was also independently associated with a longer post-ICU stay (adjusted HR,
1.6; 95% CI, 1.2-2.3; P = .009), fewer median days
alive and without mechanical ventilation (19 [interquartile range, 4-23] vs
24 [19-26]; adjusted P = .03), and a higher incidence
of cognitive impairment at hospital discharge (adjusted HR, 9.1; 95% CI, 2.3-35.3; P = .002).ConclusionDelirium was an independent predictor of higher 6-month mortality and
longer hospital stay even after adjusting for relevant covariates including
coma, sedatives, and analgesics in patients receiving mechanical ventilation.
2,590 citations