The stress response to surgery and postoperative delirium: evidence of hypothalamic-pituitary-adrenal axis hyperresponsiveness and decreased suppression of the GH/IGF-1 Axis.

INTRODUCTION: The aim of this study is to determine whether postoperative delirium is associated with dysregulation of hypothalamic-pituitary-adrenal and growth hormone/insulin-like growth factor 1 (GH/IGF-1) responses following acute systemic inflammation. METHODS: Plasma levels of cortisol, IGF-1, C-reactive protein, interleukin (IL)-6, IL-8, and IL-10 were measured before and after surgery in 101 patients ≥ 60 years without dementia undergoing elective hip arthroplasty. Participants were assessed with confusion assessment method and Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision; DSM-IV-TR) postoperatively and 37 patients fulfilled the DSM-IV-TR criteria for delirium. RESULTS: Preoperative plasma cortisol levels were similar in delirium and nondelirium groups (405.37 ± 189.04 vs 461.83 ± 219.39; P = .22). Participants with delirium had higher postoperative cortisol levels (821.67 ± 367.17 vs 599.58 ± 214.94; P = .002) with enhanced postoperative elevation in relation to baseline (1.9- vs 1.5-fold; P = .004). The plasma levels of IGF1 did not differ in delirium and nondelirium groups before (18.12 ± 7.58 vs 16.8 ± 7.86; P = .477) and following surgery (13.39 ± 5.94 vs 11.12 ± 6.2; P = .639), but the levels increased in relation to baseline more frequently in patients who developed delirium (24.3% vs 7.8%; P = .034). The magnitude of postoperative cortisol elevation correlated with ΔIL-6 (P = .485; P = .002), ΔIL-8 (P = .429; P = .008), and ΔIL-10 (P = .544; P < .001) only in patients with delirium. CONCLUSIONS: Hypothalamic-pituitary-adrenal axis hyperresponsiveness and a less frequent suppression of the GH/IGF-1 axis in response to acute stress are possibly involved in delirium pathophysiology.

Low preoperative plasma cholinesterase activity as a risk marker of postoperative delirium in elderly patients.

BACKGROUND: delirium is a frequent neuropsychiatric syndrome affecting medical and surgical elderly patients. Cholinergic dysfunction has been implicated in delirium pathophysiology and plasmatic acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities are suppressed in patients with delirium. In this cohort study, we investigated whether these changes emerge during delirium or whether they are present before its onset. METHODS: plasma activities of AChE and BuChE were measured pre- and postoperatively in consecutive patients ≥60 years old undergoing elective total hip replacement surgery. In addition to a comprehensive clinical and demographic baseline evaluation, venous blood samples were collected from each subject in the morning of hospital admission's day and in the morning of the first postoperative day. Delirium was screened daily with confusion assessment method (confirmed with diagnostic and statistical manual of mental disorders (DSM-IV)-TR). RESULTS: preoperatively, plasma esterase activity was significantly lower in patients who developed delirium compared with the remaining subjects. Following surgery BuChE activity was lower in the delirium group but this difference disappeared after controlling for preoperative values. Plasma cholinesterase activity correlated positively with calcium and haemoglobin and negatively with total bilirubin and international normalised ratio. CONCLUSION: plasma cholinesterase activity can be a useful candidate biomarker to identify subjects at greater risk of developing postoperative delirium.

The neuroinflammatory hypothesis of delirium.

Delirium is a neuropsychiatric syndrome characterized by a sudden and global impairment in consciousness, attention and cognition. It is particularly frequent in elderly subjects with medical or surgical conditions and is associated with short- and long-term adverse outcomes. The pathophysiology of delirium remains poorly understood as it involves complex multi-factorial dynamic interactions between a diversity of risk factors. Several conditions associated with delirium are characterized by activation of the inflammatory cascade with acute release of inflammatory mediators into the bloodstream. There is compelling evidence that acute peripheral inflammatory stimulation induces activation of brain parenchymal cells, expression of proinflammatory cytokines and inflammatory mediators in the central nervous system. These neuroinflammatory changes induce neuronal and synaptic dysfunction and subsequent neurobehavioural and cognitive symptoms. Furthermore, ageing and neurodegenerative disorders exaggerate microglial responses following stimulation by systemic immune stimuli such as peripheral inflammation and/or infection. In this review we explore the neuroinflammatory hypothesis of delirium based on recent evidence derived from animal and human studies.

The cholinergic system and inflammation: common pathways in delirium pathophysiology.

OBJECTIVES: To investigate whether delirium is associated with an unbalanced inflammatory response or a dysfunctional interaction between the cholinergic and immune systems. DESIGN: Cohort observational study. SETTING: General hospital orthopedic ward. PARTICIPANTS: One hundred one individuals aged 60 and older with no previous cognitive impairment undergoing elective arthroplasty. MEASUREMENTS: Incidence of postoperative delirium, plasma cholinesterase activity (acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE)) and inflammatory mediators (C-reactive protein (CRP), interleukin (IL)-1 beta, tumor necrosis factor alpha, IL-6, IL-8, IL-10) before and after surgery. RESULTS: Thirty-seven participants developed postoperative delirium and had greater production of CRP and proinflammatory to anti-inflammatory ratio after surgery. In participants with delirium, but not in controls, preoperative levels of plasma cholinesterase activity correlated with ΔCRP (AChE: ρ = 0.428, P = .008 and BuChE: ρ = 0.423, P = .009), ΔIL-6 (AChE: ρ = 0.339, P = .04), and ΔP/A ratio (AChE: ρ = 0.346, P = .04). CONCLUSION: Delirium was associated not only with an unbalanced inflammatory response, but also with a dysfunctional interaction between the cholinergic and immune systems. Comprehensive understanding of the relationship between the cholinergic and immune systems is crucial to developing new insights into delirium pathophysiology and novel therapeutic interventions.

[Cognition, social cognition and functioning in schizophrenia]. / Cognição, cognição social e funcionalidade na esquizofrenia.

The major reviews of the literature support the idea that a significant proportion of patients with schizophrenia present cognitive deficits in several domains, more marked in the domains of verbal memory, vigilance and attention, memory, intellectual quotient, language and executive functioning. Such deficits appear to be one of the main determinants of these patients' functional outcome. More recently, social cognition deficits have been described. Social cognition may be understood as a separate and independent dimension of neurocognition or non-social cognition and may constitute a mediator between the neurocognition and functioning. However, there has been controversy concerning the real meaning of deficits observed due to the diversity of analysis methodologies employed and the fact that the available neuropsychological tests and batteries have not been specifically designed to evaluate cognitive deficits in patients with schizophrenia. In this paper, the Working Group on Schizophrenia (GTE) describes and highlights the existing clinical and scientific evidence, performs a critical review of cognitive functioning, social cognition and its impact on functional outcome, in patients with schizophrenia. The authors review definitions of (neuro)cognition, social cognition and functioning, analyze the existing methods for its assessment, describe the treatments available in this context and summarize the evidence of dysfunctions in these three concepts, taking into account their interconnection. Overall, the GTE considered the need for a standardized battery of tests to measure neurocognition, social cognition and functioning, consensually accepting the use of MATRICS as the standard tool for assessing neurocognition in schizophrenia. It was also recognized that verbal memory and vigilance deficits may be the best predictors of functional outcome in schizophrenia. In addition, the GTE has established social cognition as a priority area in the study of schizophrenia, however, the limitations in terminology and assessment methodologies do not allow a consensus in this area. The GTE considers that further longitudinal studies with larger samples are needed, so that a more adequate therapeutic armamentarium becomes available for patients with schizophrenia.