Katie J. Schenning

Surgery is associated with ventricular enlargement as well as cognitive and functional decline

In preclinical studies, surgery/anesthesia contribute to cognitive decline and enhance neuropathologic changes underlying Alzheimers disease (AD). Nevertheless, the link between surgery, anesthesia, apolipoprotein E ε4 (APOE ε4), and AD remains unclear.

Isoflurane exposure leads to apoptosis of neurons and oligodendrocytes in 20- and 40-day old rhesus macaques

Previously we reported that a 5-hour exposure of 6-day-old (P6) rhesus macaques to isoflurane triggers robust neuron and oligodendrocyte apoptosis. In an attempt to further describe the window of vulnerability to anesthetic neurotoxicity, we exposed P20 and P40 rhesus macaques to 5h of isoflurane anesthesia or no exposure (control animals). Brains were collected 3h later and examined immunohistochemically to analyze neuronal and glial apoptosis. Brains exposed to isoflurane displayed neuron and oligodendrocyte apoptosis distributed throughout cortex and white matter, respectively. When combining the two age groups (P20+P40), the animals exposed to isoflurane had 3.6 times as many apoptotic cells as the control animals. In the isoflurane group, approximately 66% of the apoptotic cells were oligodendrocytes and 34% were neurons. In comparison, in our previous studies on P6 rhesus macaques, approximately 52% of the dying cells were glia and 48% were neurons. In conclusion, the present data suggest that the window of vulnerability for neurons is beginning to close in the P20 and P40 rhesus macaques, but continuing for oligodendrocytes.

Isoflurane exposure for three hours triggers apoptotic cell death in neonatal macaque brain

Background Retrospective clinical studies suggest there is a risk for neurodevelopmental impairment following early childhood exposure to anaesthesia. In the developing animal brain, including those of non-human primates (NHPs), anaesthetics induce apoptotic cell death. We previously reported that a 5 h isoflurane (ISO) exposure in infant NHPs increases apoptosis 13-fold compared with control animals. However, the majority of paediatric surgeries requiring anaesthesia are of shorter durations. We examined whether 3 h ISO exposure similarly increases neuroapoptosis in the NHP developing brain. Methods Six-day-old NHP infants ( Macaca mulatta ) were exposed to 3 h of a surgical plane of ISO ( n =6) or to room air ( n =5). Following exposure, NHP brains were screened for neuronal and oligodendrocyte apoptosis using activated caspase-3 immunolabelling and unbiased stereology. Results ISO treatment increased apoptosis (neurones + oligodendrocyte) to greater than four times that in the control group [mean density of apoptotic profiles: 57 (SD 22) mm -3 vs 14 (SD 5.2) mm -3 , respectively]. Oligodendrocyte apoptosis was evenly distributed throughout the white matter whereas neuroapoptosis occurred primarily in the cortex (all regions), caudate, putamen and thalamus. Conclusions A 3 h exposure to ISO is sufficient to induce widespread neurotoxicity in the developing primate brain. These results are relevant for clinical medicine, as many surgical and diagnostic procedures in children require anaesthesia durations similar to those modelled here. Further research is necessary to identify long-term neurobehavioural consequences of 3 h ISO exposure.

TEMPORARY REMOVAL: Recommendations for the nomenclature of cognitive change associated with anaesthesia and surgery—2018

Abstract Cognitive change affecting patients after anaesthesia and surgery has been recognised for more than 100 yr. Research into cognitive change after anaesthesia and surgery accelerated in the 1980s when multiple studies utilised detailed neuropsychological testing for assessment of cognitive change after cardiac surgery. This body of work consistently documented decline in cognitive function in elderly patients after anaesthesia and surgery, and cognitive changes have been identified up to 7.5 yr afterwards. Importantly, other studies have identified that the incidence of cognitive change is similar after non‐cardiac surgery. Other than the inclusion of non‐surgical control groups to calculate postoperative cognitive dysfunction, research into these cognitive changes in the perioperative period has been undertaken in isolation from cognitive studies in the general population. The aim of this work is to develop similar terminology to that used in cognitive classifications of the general population for use in investigations of cognitive changes after anaesthesia and surgery. A multispecialty working group followed a modified Delphi procedure with no prespecified number of rounds comprised of three face‐to‐face meetings followed by online editing of draft versions. Two major classification guidelines [Diagnostic and Statistical Manual for Mental Disorders, fifth edition (DSM‐5) and National Institute for Aging and the Alzheimer Association (NIA‐AA)] are used outside of anaesthesia and surgery, and may be useful for inclusion of biomarkers in research. For clinical purposes, it is recommended to use the DSM‐5 nomenclature. The working group recommends that ‘perioperative neurocognitive disorders’ be used as an overarching term for cognitive impairment identified in the preoperative or postoperative period. This includes cognitive decline diagnosed before operation (described as neurocognitive disorder); any form of acute event (postoperative delirium) and cognitive decline diagnosed up to 30 days after the procedure (delayed neurocognitive recovery) and up to 12 months (postoperative neurocognitive disorder).

Preoperative Cognitive and Frailty Screening in the Geriatric Surgical Patient: A Narrative Review.

PURPOSE The identification of older patients who may have deficits in cognitive or functional domains will become more pressing as increasing numbers of these patients present for preoperative evaluations. The number of older adults with deficiencies in these areas is projected to grow, and more of these patients will present for assessment in preoperative clinics with the expectation that surgeries will be performed. METHODS We review current outcomes data for preoperative cognitive impairment and frailty. FINDINGS We point to a number of directions research is taking as systems for the prevention of postoperative cognitive and functional decline are being developed. We also discuss the current status of screening and examine potential instruments that can be used in the setting of the preanesthesia clinic. IMPLICATIONS Clinicians may anticipate that geriatric screening tools focused on cognitive and functional domains will play a direct role in the ongoing evolution of presurgical assessment and triage.

Hyperglycemia abolishes the protective effect of ischemic preconditioning in glomerular endothelial cells in vitro

In preclinical investigations, ischemic preconditioning (IPC) protects kidneys from ischemia/reperfusion injury. The direct effects of IPC on glomerular endothelial cells have not been studied in detail. Most investigations of IPC have focused on healthy cells and animals, and it remains unknown whether IPC is renoprotective in the setting of medical comorbidities such as diabetes. In this study, we determined the preventive potential of IPC in healthy glomerular endothelial cell monolayers, and compared these results to monolayers cultured under hyperglycemic conditions. We exposed glomerular endothelial monolayers to 1 h of IPC 24 h prior to oxygen–glucose deprivation (OGD), an in vitro model of ischemia/reperfusion injury. Glomerular endothelial monolayer integrity was assessed by measuring transendothelial electrical resistance, albumin flux, and cell survival. We found that IPC protected healthy but not hyperglycemic glomerular endothelial monolayers from ischemia/reperfusion injury. Furthermore, not only was the protective effect of IPC lost in the setting of hyperglycemia, but IPC was actually deleterious to the integrity of hyperglycemic glomerular endothelial cell monolayers.

Postoperative Delirium: A Review of Risk Factors and Tools of Prediction

Over one-third of the surgeries in the United States are performed on patients aged 65 and older, and delirium is one of the most common postoperative complications in this population. Postoperative delirium is a heterogeneous disorder, and as such it is not surprising that the reported predisposing and precipitating factors are widely variable. Knowledge of the risk factors that predict postoperative delirium will aid in early identification of patients at highest risk in order to allow targeted use of resources including geriatric consults, specialized units, and nonpharmacologic interventions.

Sex differences in the association of alcohol with cognitive decline and brain pathology in a cohort of octogenarians

RationaleThe beneficial effects of moderate alcohol may differ in aging men versus women.ObjectivesCognitive and functional decline and neuropathology were investigated in a cohort of aging men and women with diverse alcohol histories.MethodsNon-demented (Clinical Dementia Rating (CDR) of ≤ 0.5 and a Mini-Mental State Examination (MMSE) score of > 24), autonomously living participants were tracked in longitudinal aging studies to examine self-report and objective tests of rates of decline in a cohort (n = 486) of octogenarians. Neurofibrillary tangles (NFTs; Braak stage) and neuritic plaques (NPs) were staged at autopsy in a subset of participants (n = 149) using current standard neuropathologic diagnostic criteria.ResultsModerate drinking men had an attenuated rate of decline compared to rare/never drinkers and women on the MMSE and CDR sum of boxes. In contrast, moderate drinking women had a reduced rate of decline only in the Logical Memory Delayed Recall Test (LMDR) compared to rare/never drinkers and men. Moderate alcohol consumption was associated with a reduction in the incidence of advanced (stages 5–6) Braak NFT stage in men (p < 0.05), with no effect in women.ConclusionsIn this cohort, men experienced a broader range of beneficial effects associated with alcohol. Alcohol’s effects may differ in men and women in important ways that suggest a narrower beneficial window.

The role of sex in postoperative cognitive and functional decline

unchanged after further adjustment for a large set of lifestyle, vascular and cognitive factors. In contrast, we found no relation with grey matter volumes. Conclusions: The MeDi appears to benefit brain health through preservation of structural connectivity. The strong relation of theMeDi with white matter microstructure in extensive areas with no substantial association with grey matter volumes suggests that the MeDi may benefit the brain through a favorable impact on cerebral vasculature; mediation by early vascular mechanisms deserves further research.

Caffeine Augments Anesthesia Neurotoxicity in the Fetal Macaque Brain

Caffeine is the most frequently used medication in premature infants. It is the respiratory stimulant of choice for apnea associated with prematurity and has been called the silver bullet in neonatology because of many proven benefits and few known risks. Research has revealed that sedative/anesthetic drugs trigger apoptotic death of neurons and oligodendrocytes in developing mammalian brains. Here we evaluated the influence of caffeine on the neurotoxicity of anesthesia in developing nonhuman primate brains. Fetal macaques (n = 7–8/group), at a neurodevelopmental age comparable to premature human infants, were exposed in utero for 5 hours to no drug (control), isoflurane, or isoflurane + caffeine and examined for evidence of apoptosis. Isoflurane exposure increased apoptosis 3.3 fold for neurons and 3.4 fold for oligodendrocytes compared to control brains. Isoflurane + caffeine caused neuronal apoptosis to increase 8.0 fold compared to control levels but did not augment oligoapoptosis. Neuronal death was particularly pronounced in the basal ganglia and cerebellum. Higher blood levels of caffeine within the range considered therapeutic and safe for human infants correlated with increased neuroapoptosis. Caffeine markedly augments neurotoxicity of isoflurane in the fetal macaque brain and challenges the assumption that caffeine is safe for premature infants.