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Background: Exposure of rhesus macaque fetuses for 24 h or neonates for 9 h to ketamine anesthesia causes neuroapoptosis in the developing brain. The current study clarifies the minimum exposure required for and the extent and spatial distribution of ketamine-induced neuroapoptosis in rhesus fetuses and neonates.Method: Ketamine was administered by IV infusion for 5 h to postnatal day 6 rhesus neonates or to pregnant rhesus females at 120 days' gestation (full term = 165 days). Three hours later, fetuses were delivered by cesarean section, and the fetal and neonatal brains were studied for evidence of apoptotic neurodegeneration, as determined by activated caspase-3 staining.Results: Both the fetal (n = 3) and neonatal (n = 4) ketamine-exposed brains had a significant increase in apoptotic profiles compared with drug-naive controls (fetal n = 4; neonatal n = 5). Loss of neurons attributable to ketamine exposure was 2.2 times greater in fetuses than in neonates. The pattern of neurodegeneration in fetuses was different from that in neonates, and all subjects exposed at either age had a pattern characteristic for that age.Conclusion: The developing rhesus macaque brain is sensitive to the apoptogenic action of ketamine at both a fetal and neonatal age, and exposure duration of 5 h is sufficient to induce a significant neuroapoptosis response at either age. The pattern of neurodegeneration induced by ketamine in fetuses was different from that in neonates, and loss of neurons attributable to ketamine exposure was 2.2 times greater in the fetal than neonatal brains. [ABSTRACT FROM AUTHOR]

Dysregulation of the intracellular calcium concentration is thought to play a key role in the so-called ischemic cascade, as well as for the development of cerebral vasospasm after subarachnoid haemorrhaging (SAH). Therefore, the prophylactic/therapeutic administration of cerebral calcium channel blockers for neurosurgical patients appears to be a compelling idea to prevent ischemic complications. There are abundant data on the efficacy of cerebral calcium antagonists in various animal models of central nervous system pathologies, however, very little clinical evidence exists to justify their use in humans in respective situations. So far there is only evidence for a long-term treatment effect of oral nimodipine in patients suffering from SAH, and this is based essentially on one large controlled clinical trial. Experimental results suggest that blockers of other calcium channel subtypes may be promising for future clinical roles in primary or secondary ischemic brain injury. However, it is also possible that calcium-independent mechanisms play a more important role during the development of the ischemic damage than previously assumed. Currently, there is no clinical evidence to support the prophylactic use of calcium antagonists to prevent ischemic complications in neurosurgical patients without SAH. [ABSTRACT FROM AUTHOR]

Anesthesia can influence cerebral blood flow by altering vessel diameter. Using in vivo two-photon imaging, we examined the effects of volatile anesthetics, sevoflurane and isoflurane, on vessel diameter in young and adult mice. Our results show that these anesthetics induce robust dilation of cortical arterioles and arteriole-proximate capillaries in adult mice, with milder effects in juveniles and no dilation in infants. This anesthesia-induced vasodilation correlates with decreased cytosolic Ca 2+ levels in NG2 + vascular mural cells. Optogenetic manipulation of these cells bidirectionally regulates vessel diameter, and their ablation abolishes the vasodilatory response to anesthetics. In immature brains, NG2 + mural cells are fewer in number and express lower levels of Kir6.1, a subunit of ATP-sensitive potassium channels. This likely contributes to the age-dependent differences in vasodilation, as Kir6.1 activation promotes, while its inhibition reduces, anesthesia-induced vasodilation. These findings highlight the essential role of NG2 + mural cells in mediating anesthesia-induced cerebral vasodilation., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Recent efforts to chart human brain growth across the lifespan using large-scale MRI data have provided reference standards for human brain development. However, similar models for nonhuman primate (NHP) growth are lacking. The rhesus macaque, a widely used NHP in translational neuroscience due to its similarities in brain anatomy, phylogenetics, cognitive, and social behaviors to humans, serves as an ideal NHP model. This study aimed to create normative growth charts for brain structure across the macaque lifespan, enhancing our understanding of neurodevelopment and aging, and facilitating cross-species translational research. Leveraging data from the PRIMatE Data Exchange (PRIME-DE) and other sources, we aggregated 1,522 MRI scans from 1,024 rhesus macaques. We mapped non-linear developmental trajectories for global and regional brain structural changes in volume, cortical thickness, and surface area over the lifespan. Our findings provided normative charts with centile scores for macaque brain structures and revealed key developmental milestones from prenatal stages to aging, highlighting both species-specific and comparable brain maturation patterns between macaques and humans. The charts offer a valuable resource for future NHP studies, particularly those with small sample sizes. Furthermore, the interactive open resource (https://interspeciesmap.childmind.org) supports cross-species comparisons to advance translational neuroscience research.

The concern about anesthesia-induced developmental neurotoxicity (AIDN) in infants and young children arises from animal studies indicating potential long-term neurobehavioral impairments following early-in-life anesthesia exposure. While initial clinical studies provided ambiguous results, recent prospective assessments in children indicate associations between early-in-life anesthesia exposure and later behavioral alterations. Ethical constraints and confounding factors in clinical studies pose challenges in establishing a direct causal link and in investigating its mechanisms. This commentary on a recent study in non-human primates (NHPs) focuses on exploring the role of neuroinflammation and alterations in brain functional connectivity in the behavioral impairments following early-in-life anesthesia exposure. In juvenile NHPs, chronic astrogliosis in the amygdala correlates with alterations in functional connectivity between this area with other regions of the brain and with the behavioral impairments, suggesting a potential mechanism for AIDN. Despite acknowledging the study's limitations, these findings emphasize the need for further research with larger cohorts to confirm these associations and to establish a causal link between the neuroinflammation and the behavioral alterations associated with early-in-life anesthesia exposure., Competing Interests: Declaration of Conflicting Interests The authors declare that there is no conflict of interest.

Background: Clinical studies suggest that anaesthesia exposure early in life affects neurobehavioural development. We designed a non-human primate (NHP) study to evaluate cognitive, behavioural, and brain functional and structural alterations after isoflurane exposure during infancy. These NHPs displayed decreased close social behaviour and increased astrogliosis in specific brain regions, most notably in the amygdala. Here we hypothesise that resting-state functional connectivity MRI can detect alterations in connectivity of brain areas that relate to these social behaviours and astrogliosis., Methods: Imaging was performed in 2-yr-old NHPs under light anaesthesia, after early-in-life (postnatal days 6-12) exposure to 5 h of isoflurane either one or three times, or to room air. Brain images were segmented into 82 regions of interest; the amygdala and the posterior cingulate cortex were chosen for a seed-based resting-state functional connectivity MRI analysis., Results: We found differences between groups in resting-state functional connectivity of the amygdala and the auditory cortices, medial premotor cortex, and posterior cingulate cortex. There were also alterations in resting-state functional connectivity between the posterior cingulate cortex and secondary auditory, polar prefrontal, and temporal cortices, and the anterior insula. Relationships were identified between resting-state functional connectivity alterations and the decrease in close social behaviour and increased astrogliosis., Conclusions: Early-in-life anaesthesia exposure in NHPs is associated with resting-state functional connectivity alterations of the amygdala and the posterior cingulate cortex with other brain regions, evident at the juvenile age of 2 yr. These changes in resting-state functional connectivity correlate with the decrease in close social behaviour and increased astrogliosis. Using resting-state functional connectivity MRI to study the neuronal underpinnings of early-in-life anaesthesia-induced behavioural alterations could facilitate development of a biomarker for anaesthesia-induced developmental neurotoxicity., (Copyright © 2023 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) negatively impacts the central nervous system, and studies using a full montage of electroencephalogram (EEG) electrodes have reported nonspecific EEG patterns associated with coronavirus disease 2019 (COVID-19) infection. The use of this technology is resource-intensive and limited in its implementation. In this descriptive pilot study, we report neurophysiological patterns and the potential prognostic capability of an abbreviated frontal EEG electrode montage in critically ill COVID-19 patients., Materials and Methods: Patients receiving mechanical ventilation for SARS-CoV-2 respiratory failure were monitored with Sedline Root Devices using EEG electrodes were placed over the forehead. Qualitative EEG assessments were conducted daily. The primary outcome was mortality, and secondary outcomes were duration of endotracheal intubation and lengths of intensive care and hospitalization stay., Results: Twenty-six patients were included in the study, and EEG discontinuity was identified in 22 (84.6%) patients. The limited sample size and patient heterogeneity precluded statistical analysis, but certain patterns were suggested by trends in the data. Survival was 100% (4/4) for those patients in which a discontinuous EEG pattern was not observed. The majority of patients (87.5%, 7/8) demonstrating activity in the low-moderate frequency range (7 to 17 Hz) survived compared with 61.1% (11/18) of those without this observation., Conclusions: The majority of COVID-19 patients showed signs of EEG discontinuity during monitoring with an abbreviated electrode montage. The trends towards worse survival among those with EEG discontinuity support the need for additional studies to investigate these associations in COVID-19 patients., Competing Interests: P.S.G. is a named inventor on several patents owned by Columbia University related to visualization of EEG data. His research efforts are supported in part by a grant from the James S. McDonnell Foundation ( www.jsmf.org ). The remaining authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: The authors have no conflicts of interest to disclose.

Background: Infant anaesthesia causes acute brain cell apoptosis, and later in life cognitive deficits and behavioural alterations, in non-human primates (NHPs). Various brain injuries and neurodegenerative conditions are characterised by chronic astrocyte activation (astrogliosis). Glial fibrillary acidic protein (GFAP), an astrocyte-specific protein, increases during astrogliosis and remains elevated after an injury. Whether infant anaesthesia is associated with a sustained increase in GFAP is unknown. We hypothesised that GFAP is increased in specific brain areas of NHPs 2 yr after infant anaesthesia, consistent with prior injury., Methods: Eight 6-day-old NHPs per group were exposed to 5 h isoflurane once (1×) or three times (3×), or to room air as a control (Ctr). Two years after exposure, their brains were assessed for GFAP density changes in the primary visual cortex (V1), perirhinal cortex (PRC), hippocampal subiculum, amygdala, and orbitofrontal cortex (OFC). We also assessed concomitant microglia activation and hippocampal neurogenesis., Results: Compared with controls, GFAP densities in V1 were increased in exposed groups (Ctr: 0.208 [0.085-0.427], 1×: 0.313 [0.108-0.533], 3×: 0.389 [0.262-0.652]), whereas the density of activated microglia was unchanged. In addition, GFAP densities were increased in the 3× group in the PRC and the subiculum, and in both exposure groups in the amygdala, but there was no increase in the OFC. There were no differences in hippocampal neurogenesis among groups., Conclusions: Two years after infant anaesthesia, NHPs show increased GFAP without concomitant microglia activation in specific brain areas. These long-lasting structural changes in the brain caused by infant anaesthesia exposure may be associated with functional alterations at this age., (Copyright © 2021 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Purpose of Review: Long-term behavioural and cognitive impairments after exposure to general anaesthetics during infancy is an intensely investigated and controversial topic. Recent clinical studies with prospective assessments associate exposure with long-term behavioural alterations rather than cognitive impairments. This review aims to provide an understanding of the long-term cognitive impairments and behavioural alterations found in recent animal studies and to summarize latest advances in strategies to protect against anaesthesia-induced developmental neurotoxicity (AIDN)., Recent Findings: Preclinical studies, particularly those in nonhuman primates (NHPs), provide accumulating evidence that anaesthesia exposure during infancy is associated with long-term alterations in behaviour, but cognitive impairments are more controversial. Results from recent studies aiming to find mitigating strategies to reduce AIDN or to identify alternative anaesthetic agents include the co-administration of dexmedetomidine with the anaesthetic drugs or the alternative use of hypnotic neurosteroids without being harmful to the developing brain., Summary: Recent findings in animal studies with translational relevance support the proposed association between early-in-life anaesthesia exposure and long-term alterations in behaviour. Studies aiming to prevent AIDN are promising and need evaluation in the NHP model. The careful design of subsequent translational studies will be critical to advance the field forward towards safer anaesthesia exposure in children., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Both animal and retrospective human studies have linked extended and repeated general anaesthesia during early development with cognitive and behavioural deficits later in life. However, the neuronal circuit mechanisms underlying this anaesthesia-induced behavioural impairment are poorly understood., Methods: Neonatal mice were administered one or three doses of propofol, a commonly used i.v. general anaesthetic, over Postnatal days 7-11. Control mice received Intralipid® vehicle injections. At 4 months of age, the mice were subjected to a series of behavioural tests, including motor learning. During the process of motor learning, calcium activity of pyramidal neurones and three classes of inhibitory interneurones in the primary motor cortex were examined in vivo using two-photon microscopy., Results: Repeated, but not a single, exposure of neonatal mice to propofol i.p. caused motor learning impairment in adulthood, which was accompanied by a reduction of pyramidal neurone number and activity in the motor cortex. The activity of local inhibitory interneurone networks was also altered: somatostatin-expressing and parvalbumin-expressing interneurones were hypoactive, whereas vasoactive intestinal peptide-expressing interneurones were hyperactive when the mice were performing a motor learning task. Administration of low-dose pentylenetetrazol to attenuate γ-aminobutyric acid A receptor-mediated inhibition or CX546 to potentiate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-subtype glutamate receptor function during emergence from anaesthesia ameliorated neuronal dysfunction in the cortex and prevented long-term behavioural deficits., Conclusions: Repeated exposure of neonatal mice to propofol anaesthesia during early development causes cortical circuit dysfunction and behavioural impairments in later life. Potentiation of neuronal activity during recovery from anaesthesia reduces these adverse effects of early-life anaesthesia., (Copyright © 2021 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

The coronavirus disease 2019 (COVID-19) pandemic has impacted many aspects of neuroscience research. At the 2020 Society of Neuroscience in Anesthesiology and Critical Care (SNACC) Annual Meeting, the SNACC Research Committee met virtually to discuss research challenges encountered during the COVID-19 pandemic along with possible strategies for facilitating research activities. These challenges and recommendations are included in this Consensus Statement. The objectives are to: (1) provide an overview of the disruptions and challenges to neuroscience research caused by the COVID-19 pandemic, and; (2) put forth a set of consensus recommendations for strengthening research sustainability during and beyond the current pandemic. Specific recommendations are highlighted for adapting laboratory and human subject study activities to optimize safety. Complementary research activities are also outlined for both laboratory and clinical researchers if specific investigations are impossible because of regulatory or societal changes. The role of virtual platforms is discussed with respect to fostering new collaborations, scheduling research meetings, and holding conferences such that scientific collaboration and exchange of ideas can continue. Our hope is for these recommendations to serve as a valuable resource for investigators in the neurosciences and other research disciplines for current and future research disruptions., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Clinical studies show that children exposed to anaesthetics for short times at young age perform normally on intelligence tests, but display altered social behaviours. In non-human primates (NHPs), infant anaesthesia exposure for several hours causes neurobehavioural impairments, including delayed motor reflex development and increased anxiety-related behaviours assessed by provoked response testing. However, the effects of anaesthesia on spontaneous social behaviours in juvenile NHPs have not been investigated. We hypothesised that multiple, but not single, 5 h isoflurane exposures in infant NHPs are associated with impairments in specific cognitive domains and altered social behaviours at juvenile age., Methods: Eight Rhesus macaques per group were anaesthetised for 5 h using isoflurane one (1×) or three (3×) times between postnatal days 6 and 12 or were exposed to room air (control). Cognitive testing, behavioural assessments in the home environment, and provoked response testing were performed during the first 2 yr of life., Results: The cognitive functions tested did not differ amongst groups. However, compared to controls, NHPs in the 3× group showed less close social behaviour (P=0.016), and NHPs in the 1× group displayed increased anxiety-related behaviours (P=0.038) and were more inhibited towards novel objects (P<0.001)., Conclusions: 5 h exposures of NHPs to isoflurane during infancy are associated with decreased close social behaviour after multiple exposures and more anxiety-related behaviours and increased behavioural inhibition after single exposure, but they do not affect the cognitive domains tested. Our findings are consistent with behavioural alterations in social settings reported in clinical studies, which may guide future research., Competing Interests: Declarations of interest The authors declare that they have no conflicts of interest., (Copyright © 2020 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Background: Preclinical studies suggest that exposures of infant animals to general anesthetics cause acute neurotoxicity and affect their neurobehavioral development representing a potential risk to human infants undergoing anesthesia. Alternative or mitigating strategies to counteract such adverse effects are desirable. Dexmedetomidine (DEX) is a clinically established sedative with potential neuroprotective properties. DEX ameliorates experimental brain injury as well as neurotoxicity caused by anesthetic doses of sevoflurane (SEVO) or other general anesthetics in infant animals. However, it is unknown whether DEX also is beneficial when given together with lower doses of these drugs. Here we tested the hypothesis that DEX co-administration with a sub-anesthetic dose of SEVO reduces responsiveness to external stimuli while also protecting against SEVO-induced brain cell apoptosis., Method: Rats were exposed on postnatal day 7 for 6 h to SEVO 1.1, 1.8, or 2.5% and were given intraperitoneal injections of saline or DEX at different doses (1-25 μg/kg) three times during the exposure. Responsiveness to external stimuli, respiratory rates, and blood gases were assessed. Apoptosis was determined in cortical and subcortical brain areas by activated caspase-3 immunohistochemistry., Results: Rats exposed to SEVO 1.1% alone were sedated but still responsive to external stimuli whereas those exposed to SEVO 1.8% reached complete unresponsiveness. SEVO-induced brain cell apoptosis increased dose-dependently, with SEVO 1.1% causing a small increase in apoptosis above that in controls. Co-administration of DEX at 1 μg/kg did not alter the responsiveness to stimuli nor the apoptosis induced by SEVO 1.1%. In contrast, co-administration of DEX at 5 μg/kg or higher with SEVO 1.1% reduced responsiveness but potentiated apoptosis., Conclusions: In the neonatal rat model, co-administration of a clinically relevant dose of DEX (1 μg/kg) with a sub-anesthetic dose of SEVO (1.1%) does not affect the neurotoxicity of the anesthetic while co-administration of higher doses of DEX with SEVO 1.1% potentiates it., Competing Interests: Declaration of Competing Interest The authors report no declarations of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In March 2019, SmartTots, a public-private partnership between the US Food and Drug Administration and the International Anesthesia Research Society, hosted a meeting attended by research experts, anaesthesia journal editors, and government agency representatives to discuss the continued need for rigorous preclinical research and the importance of establishing reporting standards for the field of anaesthetic perinatal neurotoxicity. This group affirmed the importance of preclinical research in the field, and welcomed novel and mechanistic approaches to answer some of the field's largest questions. The attendees concluded that summarising the benefits and disadvantages of specific model systems, and providing guidance for reporting results, would be helpful for designing new experiments and interpreting results across laboratories. This expert opinion report is a summary of these discussions, and includes a focused review of current animal models and reporting standards for the field of perinatal anaesthetic neurotoxicity. This will serve as a practical guide and road map for novel and rigorous experimental work., (Copyright © 2020 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

In the section of "Developmental Neurotoxicity: An Update" of the Pediatric Anesthesia Neurodevelopmental Assessment (PANDA) symposium 2018 the speakers presented the current literature in translational and clinical research. Dr. Brambrink spoke about translational research in anesthetic neurotoxicity, beginning with discovery in the rodent model, then focusing on evidence from nonhuman primates. Dr. Waspe applied the methodology of Adverse Outcome Pathways from the field of toxicology to developmental neurotoxicity of anesthetics. Dr. O'Leary presented relevant clinical studies that were published in 2017 divided by a focus on academic performance, clinical outcomes or diagnoses, or neuropsychological testing.

All commonly used general anesthetics have been shown to cause neurotoxicity in animal models, including nonhuman primates. Opinion, however, remains divided over how cumulative evidence from preclinical and human studies in this field should be interpreted and its translation to current practices in pediatric anesthesia and surgery. A group of international experts in laboratory and clinical sciences recently convened in Genoa, Italy, to evaluate the current state of both laboratory and clinical research and discuss future directions for basic, translational, and clinical studies in this field. This paper describes those discussions and conclusions. A central goal identified was the importance of continuing to pursue laboratory research efforts to better understand the biological pathways underlying anesthesia neurotoxicity. The distinction between basic and translational experimental designs in this field was highlighted, and it was acknowledged that it will be important for future animal research to try to causally link structural changes with long-term cognitive abnormalities. While inherent limitations will continue to affect the ability of even large observational cohorts to determine if anesthesia impacts neurodevelopment or behavioral outcomes, the importance of conducting further large well-designed cohort studies was also emphasized. Adequately powered cohorts could clarify which populations are at increased risk, provide information on environmental and healthcare-related risk modifiers, and guide future interventional trials. If anesthetics cause structural or functional adverse neurological effects in young children, alternative or mitigating strategies need to be considered. While protective or mitigating strategies have been repeatedly studied in animals, there are currently no human data to support alternative anesthetic strategies in clinical practice. Lastly, it was noted that there is still considerable debate over the clinical relevance of anesthesia neurotoxicity, and the need to evaluate the impact of other aspects of perioperative care on neurodevelopment must also be considered., (© 2018 John Wiley & Sons Ltd.)

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.

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., (© The Author 2017. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Background: Exposure of infant animals to clinically used anaesthetics is associated with acute structural brain abnormalities and development functional alterations. The α 2 -adrenoceptor agonist dexmedetomidine (DEX) induces sedation, analgesia, and provides neuroprotection in experimental brain injury models. However, it is unknown whether DEX also affords protection in the developing brain against anaesthesia using sevoflurane (SEVO), which is commonly used in paediatric anaesthesia., Methods: Infant rats were exposed on postnatal day seven for six h to 2.5% SEVO and were given i.p. injections of saline or DEX (1-50 µg kg -1 ) three times during the exposure. Level of anaesthesia, respiratory rates, and arterial blood gasses were assessed for each animal. Apoptosis was determined in brain slices immunostained for activated caspase-3 (AC-3) using a computerised approach., Results: SEVO alone induced a surgical plane of anaesthesia, and all animals survived the study. SEVO induced an approximately 10-fold increase in AC-3 positive cells in several cortical and subcortical brain regions compared with untreated control animals. Co-administration of DEX 1 µg kg -1 with SEVO significantly reduced apoptosis in all brain areas, affording the highest protection in the thalamus (84% reduction) and lowest in the hippocampus and cortical areas (∼50% reduction). DEX 5-25 µg kg -1 plus SEVO dose-dependently increased infant rat mortality., Conclusions: SEVO anaesthesia induced widespread apoptosis in infant rat brain. Co-administration of DEX (1 µg kg -1 ) provided significant protection, whereas DEX (5 µg kg -1 or higher) plus SEVO increased mortality. Our findings suggest that DEX could be an attractive therapeutic for future studies investigating its neuroprotective potential in a translational animal model., (© The Author 2017. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

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., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Experimental evidence correlates anesthetic exposure during early development with neuronal and glial injury and death, as well as behavioral and cognitive impairments, in young animals. Several, although not all, retrospective human studies of neurocognitive and behavioral disorders after childhood exposure to anesthesia suggest a similar association. Few studies have specifically investigated the effects of infant anesthesia exposure on subsequent neurobehavioral development. Using a highly translational nonhuman primate model, the authors investigated the potential dose-dependent effects of anesthesia across the first year of development., Methods: The authors examined the effects of single or multiple early postnatal isoflurane exposures on subsequent behavioral development in 24 socially reared rhesus macaques. Infants were exposed to 5 h of isoflurane anesthesia once, three times (ISO-3), or not at all (control). The authors assessed reflex development and anxiety using standardized tests. At approximately 1 yr, infants (n = 23) were weaned and housed indoors with 5 to 6 other subjects. The authors recorded their response to this move and reassessed anxiety., Results: Compared to controls, animals exposed to repeated isoflurane (ISO-3) presented with motor reflex deficits at 1 month (median [range]: ISO-3 = 2 [1 to 5] vs. control = 5 [3 to 7]; P < 0.005) and responded to their new social environment with increased anxiety (median [range]: ISO-3 = 0.4 bouts/min [0.2 to 0.6]; control = 0.25 bouts/min [0.1 to 0.3]; P = 0.05) and affiliative/appeasement behavior (median [range]: ISO-3 = 0.1 [0 to 0.2]; control = 0 bouts/min [0 to 0.1]; P < 0.01) at 12 months. There were no statistically significant behavioral alterations after single isoflurane exposure., Conclusions: Neonatal exposure to isoflurane, particularly when repeated, has long-term behavioral consequences affecting both motor and socioemotional aspects of behavior., Competing Interests: None of the authors have any conflict of interest.

Background: Multiple attempts at tracheal intubation are associated with mortality, and successful rescue requires a structured plan. However, there remains a paucity of data to guide the choice of intubation rescue technique after failed initial direct laryngoscopy. The authors studied a large perioperative database to determine success rates for commonly used intubation rescue techniques., Methods: Using a retrospective, observational, comparative design, the authors analyzed records from seven academic centers within the Multicenter Perioperative Outcomes Group between 2004 and 2013. The primary outcome was the comparative success rate for five commonly used techniques to achieve successful tracheal intubation after failed direct laryngoscopy: (1) video laryngoscopy, (2) flexible fiberoptic intubation, (3) supraglottic airway as part of an exchange technique, (4) optical stylet, and (5) lighted stylet., Results: A total of 346,861 cases were identified that involved attempted tracheal intubation. A total of 1,009 anesthesia providers managed 1,427 cases of failed direct laryngoscopy followed by subsequent intubation attempts (n = 1,619) that employed one of the five studied intubation rescue techniques. The use of video laryngoscopy resulted in a significantly higher success rate (92%; 95% CI, 90 to 93) than other techniques: supraglottic airway conduit (78%; 95% CI, 68 to 86), flexible bronchoscopic intubation (78%; 95% CI, 71 to 83), lighted stylet (77%; 95% CI, 69 to 83), and optical stylet (67%; 95% CI, 35 to 88). Providers most frequently choose video laryngoscopy (predominantly GlideScope [Verathon, USA]) to rescue failed direct laryngoscopy (1,122/1,619; 69%), and its use has increased during the study period., Conclusions: Video laryngoscopy is associated with a high rescue intubation success rate and is more commonly used than other rescue techniques.

Background: Tracheal intubation using acute-angle videolaryngoscopy achieves high success rates, but is not without difficulty. We aimed to determine predictors of 'difficult videolaryngoscopy'., Methods: We performed a secondary analysis of a data set (n=1100) gathered from a multicentre prospective randomized controlled trial of patients for whom difficult direct laryngoscopy was anticipated and who were intubated with one of two videolaryngoscopy devices (GlideScope(®) or C-MAC(®) with D-blade). 'Difficult videolaryngoscopy' was defined as 'first intubation time >60 s' or 'first attempt intubation failure'. A multivariate logistic regression model along with stepwise model selection techniques was performed to determine independent predictors of difficult videolaryngoscopy., Results: Of 1100 patients, 301 were identified as difficult videolaryngoscopies. By univariate analysis, head and neck position, provider, type of surgery, and mouth opening were associated with difficult videolaryngoscopy (P<0.05). According to the multivariate logistic regression model, characteristics associated with greater risk for difficult videolaryngoscopy were as follows: (i) head and neck position of 'supine sniffing' vs 'supine neutral' {odds ratio (OR) 1.63, 95% confidence interval (CI) [1.14, 2.31]}; (ii) undergoing otolaryngologic or cardiac surgery vs general surgery (OR 1.89, 95% CI [1.19, 3.01] and OR 6.13, 95% CI [1.85, 20.37], respectively); (iii) intubation performed by an attending anaesthestist vs a supervised resident (OR 1.83, 95% CI [1.14, 2.92]); and (iv) small mouth opening (OR 1.18, 95% CI [1.02, 1.36])., Conclusion: This secondary analysis of an existing data set indicates four covariates associated with difficult acute-angle videolaryngoscopy, of which patient position and provider level are modifiable., (© The Author 2016. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Exposure of infant animals, including non-human primates (NHPs), to anaesthetic drugs causes apoptotic death of neurons and oligodendrocytes (oligos) and results in long-term neurodevelopmental impairment (NDI). Moreover, retrospective clinical studies document an association between anaesthesia exposure of human infants and significant increase in NDI. These findings pose a potentially serious dilemma because millions of human infants are exposed to anaesthetic drugs every year as part of routine medical care. Lithium (Li) at clinically established doses is neuroprotective in various cerebral injury models. We therefore investigated whether Li also protects against anaesthesia neurotoxicity in infant NHPs. On postnatal day 6 NHPs were anaesthetized with the widely used anaesthetic isoflurane (ISO) for 5 h employing the same standards as in a human pediatric surgery setting. Co-administration of Li completely prevented the acute ISO-induced neuroapoptosis and significantly reduced ISO-induced apoptosis of oligodendroglia. Our findings are highly encouraging as they suggest that a relatively simple pharmacological manipulation might protect the developing primate brain against the neurotoxic action of anaesthetic drugs while not interfering with the beneficial actions of these drugs. Further research is needed to determine Li's potential to prevent long-term NDI resulting from ISO anaesthesia, and to establish its safety in human infants.

Background: Intubation success in patients with predicted difficult airways is improved by video laryngoscopy. In particular, acute-angle video laryngoscopes are now frequently chosen for endotracheal intubation in these patients. However, there is no evidence concerning whether different acute-angle video laryngoscopes can be used interchangeably in this scenario and would allow endotracheal intubation with the same success rate. We therefore tested whether first-attempt intubation success is similar when using a newly introduced acute-angle blade, that is an element of an extended airway management system (C-MAC D-Blade) compared with a well-established acute-angle video laryngoscope (GlideScope)., Methods: In this large multicentered prospective randomized controlled noninferiority trial, patients requiring general anesthesia for elective surgery and presenting with clinical predictors of difficult laryngoscopy were randomly assigned to intubation using either the C-MAC D-Blade or the GlideScope video laryngoscope. The hypothesis was that first-attempt intubation success using the new device (D-Blade) is no >4% less than the established device (GlideScope), which would determine noninferiority of the new instrument versus the established instrument. The secondary outcomes we observed included intubation success with multiple attempts and airway-related complications within 7 days of enrollment., Results: Eleven hundred patients were randomly assigned to either video laryngoscope. Intubation success rate on first attempt was 96.2% in the GlideScope group and 93.4% in the C-MAC D-Blade group. Although the absolute difference between the 2 groups was only 2.8%, the 90.35% upper confidence limit of the difference exceeded the predefined margin (4.98%), indicating a rejection of the noninferiority hypothesis for first-attempt intubation success. For attending anesthesiologists, and upon multiple attempts, intubation success did not differ between systems. Pharyngeal injury was noted in 1% of the patients, and the incidence did not differ between interventional groups., Conclusions: Head-to-head comparison in this large multicenter trial revealed that the newly introduced C-MAC D-Blade does not yield the same first-attempt intubation success as the GlideScope in patients with predicted difficult laryngoscopy except in the hands of attending anesthesiologists. Additional research would be necessary to identify potential causes for this difference. Intubation success rates were very high with both systems, indicating that acute-angle video laryngoscopy is an exceptionally successful strategy for the initial approach to endotracheal intubation in patients with predicted difficult laryngoscopy.

Large hemispheric infarction (LHI), also known as malignant middle cerebral infarction, is a devastating disease associated with significant disability and mortality. Clinicians and family members are often faced with a paucity of high quality clinical data as they attempt to determine the most appropriate course of treatment for patients with LHI, and current stroke guidelines do not provide a detailed approach regarding the day-to-day management of these complicated patients. To address this need, the Neurocritical Care Society organized an international multidisciplinary consensus conference on the critical care management of LHI. Experts from neurocritical care, neurosurgery, neurology, interventional neuroradiology, and neuroanesthesiology from Europe and North America were recruited based on their publications and expertise. The panel devised a series of clinical questions related to LHI, and assessed the quality of data related to these questions using the Grading of Recommendation Assessment, Development and Evaluation guideline system. They then developed recommendations (denoted as strong or weak) based on the quality of the evidence, as well as the balance of benefits and harms of the studied interventions, the values and preferences of patients, and resource considerations.

Isoflurane, ketamine, and propofol are common anesthetics in human and nonhuman primate medicine. However, scant normative data exist regarding the response of neonatal macaques to these anesthetics. We compared the effects of isoflurane, ketamine, and propofol anesthesia on physiologic parameters in neonatal rhesus macaques. Neonatal rhesus macaques (age, 5 to 7 d) were exposed to isoflurane (n = 5), ketamine (n = 4), propofol (n = 4) or no anesthesia (n = 5) for 5 h. The anesthetics were titrated to achieve a moderate anesthetic plane, and heart rate, blood pressure, respiratory rate, end tidal carbon dioxide, oxygen saturation, and temperature were measured every 15 min. Venous blood samples were collected to determine blood gases and metabolic status at baseline, 0.5, 2.5, and 4.5 h after induction and at 3 h after the end of anesthesia. Compared with ketamine, isoflurane caused more hypotensive events and necessitated the administration of increased volumes of intravenous fluids to support blood pressure throughout anesthesia; no significant differences were observed between the isoflurane and propofol groups for these parameters. In addition, isoflurane resulted in a significantly shorter average time to extubation, compared with both ketamine and propofol. Due to supportive care, other physiologic variables remained stable between anesthetic regimens and throughout the 5-h exposure. These data improve our understanding of the effects of these 3 anesthetics in neonatal rhesus macaques and will aid veterinarians and researchers as they consider the risks and benefits of and resources required during general anesthesia in these animals.

Although androgens are reported to affect stroke outcomes by altering ischemic tissue damage, their effect on post-injury repair is unknown. Since neurogenesis has recently been recognized as contributing to stroke outcomes, we investigated the role of androgens on stroke-induced neurogenesis. Adult male mice were subjected to transient middle cerebral artery occlusion (MCAO) and neurogenesis was examined 1 week later by quantifying BrdU/doublecortin-positive and BrdU/NeuN-positive neurons in brain germinal regions as well as the injured striatum. To elucidate the role of endogenous androgens, post-MCAO neurogenesis was examined in gonadally intact males, intact males implanted with the androgen receptor antagonist flutamide, and surgically castrated males. Surgical castration or pharmacologic androgen receptor blockade had no effects on post-ischemic neurogenesis, except that continuous androgen receptor blockade unexpectedly suppressed maturation of newborn neurons (BrdU/NeuN-positive cells) in the dentate gyrus. Post-MCAO neurogenesis was also examined in surgically castrated mice treated with continuous release implants containing testosterone or dihydrotestosterone (DHT). Testosterone and DHT robustly inhibited post-ischemic neurogenesis in the dentate gyrus, and the more potent androgen DHT virtually abolished the presence of immature newborn neurons (BrdU/doublecortin-positive cells) in the injured striatum. Our data suggest that endogenous androgens do not alter post-stroke neurogenesis quantitatively, but the presence of supra-physiological androgen stimulation profoundly suppresses early neurogenesis in germinal brain areas and reduces cellular repair in injured tissue after cerebral ischemia. These results advance the understanding of the role that androgens play in stroke outcomes.

Background: General anesthesia (GA) for acute stroke interventions may be associated with inferior functional outcomes. Our goal was to identify physiologic parameters that mediate this association., Methods: Consecutive patients treated at our institution between August 2007 and December 2010 were identified from a prospective database. Clinical data were then extracted by retrospective chart review. Variables significantly associated with outcome in univariate analysis were also examined in multivariate analysis, controlling for well-established prespecified predictors of functional outcome., Results: Of the 106 patients identified, 20 were excluded (17 due to the absence of 90-day mRS and 3 due to insufficient anesthetic records). Blood pressure (BP) decreased significantly after induction of GA, but there was no association between BP and outcome. End tidal carbon dioxide values (ETCO2) at 60 and 90 min, however, were significantly associated with outcomes in both univariate and multivariate analyses. Mean ETCO2 in patients with favorable outcomes (modified Rankin Scale (mRS) 0-3) was higher than in those with unfavorable outcomes (mRS 4-6): 35.2 mmHg versus 32.2 (p = 0.03) at 60 min and 34.9 versus 31.9 (p = 0.04) at 90 min. The adjusted odds ratios for poor outcomes for each 1 mmHg decrease in ETCO2 were the same: 0.76 (95 % CI 0.65-0.92; p = 0.004) at 60 min and 0.76 (95 % CI 0.61-0.93; p = 0.01) at 90 min., Conclusions: While BP decreased significantly in patients undergoing GA for acute stroke intervention, it did not correlate with patient outcome. Decreases in ETCO2 at 30 and 60 min, however, were associated with 90-day mRS.

Background: The authors have previously shown that exposure of the neonatal nonhuman primate (NHP) brain to isoflurane for 5 h causes widespread acute apoptotic degeneration of neurons and oligodendrocyte. The current study explored the potential apoptogenic action of isoflurane in the fetal NHP brain., Methods: Fetal rhesus macaques at gestational age of 120 days (G120) were exposed in utero for 5 h to isoflurane anesthesia (n = 5) or to no anesthesia (control condition; n = 4), and all regions of the brain were systematically evaluated 3 h later for evidence of apoptotic degeneration of neurons or glia., Results: Exposure of the G120 fetal NHP brain to isoflurane caused a significant increase in apoptosis of neurons and of oligodendrocytes at a stage when oligodendrocytes were just beginning to myelinate axons. The neuroapoptosis response was most prominent in the cerebellum, caudate, putamen, amygdala, and several cerebrocortical regions. Oligodendrocyte apoptosis was diffusely distributed over many white matter regions. The total number of apoptotic profiles (neurons + oligodendrocytes) in the isoflurane-exposed brains was increased 4.1-fold, compared with the brains from drug-naive controls. The total number of oligodendrocytes deleted by isoflurane was higher than the number of neurons deleted., Conclusions: Isoflurane anesthesia for 5 h causes death of neurons and oligodendrocytes in the G120 fetal NHP brain. In the fetal brain, as the authors previously found in the neonatal NHP brain, oligodendrocytes become vulnerable when they are just achieving myelination competence. The neurotoxic potential of isoflurane increases between the third trimester (G120) and the neonatal period in the NHP brain.

Background: A group of anesthesiologists practice as intensivists in neurointensive care units (NeuroICU). The current nature and implications of the role of anesthesiology-based neurointensivist remain unclear. The purpose of this survey was to assess today's practice environment of anesthesiology-based neurointensivists as a framework for future study., Methods: During the period between January 2011 and March 2011, we identified anesthesiologists who provide patient care in specialized NeuroICUs in the United States. We used an online, 15-question survey to gauge the environment and their role in the delivery of care to critically ill patients admitted to NeuroICUs., Results: Of the 104 NeuroICUs in the United States, 22 institutions include anesthesiology-based neurointensivists (n=41). With a response from 33 of 41 requested surveys, anesthesiology-based neurointensivists reported that background training and roles for providing patient care in the NeuroICU setting varied widely between institutions. In contrast, these practices were similar in providing 24-hour coverage (76%), working with neurosurgical (88%) and anesthesiology residents (85%), and having critical-care fellowship training (97%). Almost all surveyed individuals practice both neurocritical care and anesthesia in the operating room, and 76% reported satisfaction with their working environment in the NeuroICU relative to other responsibilities., Conclusions: Anesthesiology-based neurointensivists currently represent a small subgroup within the rapidly growing neurointensivist workforce in the United States and consider neurocritical care a valuable aspect of their career. Promoting subspecialty training in neurocritical care among anesthesiologists may provide an opportunity for new patient-care frontiers and address the increasing need for NeuroICU physicians.

Purpose of Review: Sedation and anesthesia are often necessary for children at any age, and are frequently provided in ambulatory settings. Concerns have mounted, based on both laboratory studies including various mammalian species and retrospective human clinical studies, that the very drugs that induce sedation and anesthesia may trigger an injury in the developing brain, resulting in long-lasting neurobehavioral consequences., Recent Findings: New retrospective studies further augment these concerns. Specifically, recent studies support that a single anesthesia exposure before age 3 may increase the risk for long-term disabilities in language acquisition and abstract reasoning, and that exposure to two or more anesthetics before age 2 nearly doubles the risk for an attention-deficit hyperactivity disorder diagnosis by age 19. However, methodological limitations preclude final conclusions or change in practice based on these reports, as retrospective studies cannot prove causation. Ongoing prospective clinical studies such as 'General Anesthesia and Apoptosis Study', 'Pediatric Anesthesia NeuroDevelopment Assessment', and 'Mayo Safety in Kids' trials will offer more answers in the future. Meanwhile, laboratory experiments continue to describe differential morphologic injury to individual structures in the neuropil, and have identified mitochondrial dysfunction and neuroinflammation as potential links in the injury process. Additionally, concepts for protection against anesthesia-induced neurotoxicity continue to be tested in the laboratory., Summary: Results from ongoing prospective clinical trials and translational research will help clarify whether anesthesia-associated neurotoxicity affects the developing human brain, including whether it causes long-term disability, and may further identify the injury mechanisms and potential strategies for protection. Currently, the available evidence does not support a change in practice.

Purpose of Review: Every year, millions of children undergo anesthesia. Emerging evidence from experimental in-vitro and in-vivo models supports a role for neuropathologic injury and neurobehavioral deficits at older age after early exposure to various anesthetic regimens. Clinical studies have sought to identify a phenotype of developmental anesthesia neurotoxicity in humans, but the current evidence is limited to data from retrospective studies with their associated confounders. Experimental models have been used to further define the injury and to help identify potential mechanisms of this neurotoxicity., Recent Findings: A recent clinical trial from an Australian birth cohort suggests a single anesthesia exposure as a neonate or infant may increase the risk for language and abstract reasoning deficits later in life, though residual data confounders may remain. Several ongoing clinical trials like Mayo Safety in Kids, Pediatric Anesthesia NeuroDevelopment Assessment, and General Anesthesia and Apoptosis Study will likely offer more clear answers in the future. In the interim, experimental models have described roles for neuroinflammation, mitochondrial damage from reactive oxygen species, and the presence of several neuronal morphology changes from anesthesia exposure. Additionally, several potential neuroprotective agents and strategies have been tested in the laboratory., Summary: Whether anesthesia-associated neurotoxicity affects the developing human brain and whether this leads to clinically measurable deficits remains unclear.

Objective: Previously we reported that exposure of 6-day-old (P6) rhesus macaques to isoflurane for 5 hours triggers a robust neuroapoptosis response in developing brain. We have also observed (unpublished data) that isoflurane causes apoptosis of cellular profiles in the white matter that resemble glia. We analyzed the cellular identity of the apoptotic white matter profiles and determined the magnitude of this cell death response to isoflurane., Methods: Neonatal (P6) rhesus macaques were exposed for 5 hours to isoflurane anesthesia according to current clinical standards in pediatric anesthesia. Brains were collected 3 hours later and examined immunohistochemically to analyze apoptotic neuronal and glial death., Results: Brains exposed to isoflurane displayed significant apoptosis in both the white and gray matter throughout the central nervous system. Approximately 52% of the dying cells were glia, and 48% were neurons. Oligodendrocytes (OLs) engaged in myelinogenesis were selectively vulnerable, in contrast to OL progenitors, astrocytes, microglia, and interstitial neurons. When adjusted for control rates of OL apoptosis, the percentage of OLs that degenerated in the forebrain white matter of the isoflurane-treated group was 6.3% of the total population of myelinating OLs., Interpretation: Exposure of the infant rhesus macaque brain to isoflurane for 5 hours is sufficient to cause widespread apoptosis of neurons and OLs throughout the developing brain. Deletion of OLs at a stage when they are just beginning to myelinate axons could potentially have adverse long-term neurobehavioral consequences that might be additive to the potential consequences of isoflurane-induced neuroapoptosis., (Copyright © 2012 American Neurological Association.)

We evaluated the performance of tracheal intubation using video laryngoscopy in an obstetric unit. We analyzed airway management details during a 3-year period, and observed 180 intubations. All cases were managed with direct or video laryngoscopy. Direct laryngoscopy resulted in 157 out of 163 (95% confidence interval [CI], 92%-99%) first attempt successful intubations and failed once. Video laryngoscopy resulted in 18 of 18 (95% CI, 81%-100%) successful intubations on first attempt. The failed direct laryngoscopy was rescued with video laryngoscopy. The patients managed with video laryngoscopy frequently required urgent or emergency surgery and had predictors of difficult direct laryngoscopy in 16 of 18 cases. Video laryngoscopy may be a useful adjunct for obstetric airway management, and its role in this difficult airway scenario should be further studied.

Concerns for toxic effects of anesthesia to the brains of the young and the elderly are mounting. While experimental evidence for such effects in the developing brain is strong, the underlying mechanisms are less well understood and debate continues as to whether young humans are at risk for anesthetic neurotoxicity. The phenomenon of postoperative cognitive deterioration in the elderly remains controversial. Time course, severity, and whether or not it persists long term are under debate. For both patient groups, today's evidence is not sufficient to guide change in clinical practice. Well-designed research is therefore imperative to tackle this critical issue., (Copyright © 2012. Published by Elsevier Inc.)