Peri-Operative Risk Factors Associated with Post-Operative Cognitive Dysfunction (POCD): An Umbrella Review of Meta-Analyses of Observational Studies.

This umbrella review aimed to systematically identify the peri-operative risk factors associated with post-operative cognitive dysfunction (POCD) using meta-analyses of observational studies. To date, no review has synthesised nor assessed the strength of the available evidence examining risk factors for POCD. Database searches from journal inception to December 2022 consisted of systematic reviews with meta-analyses that included observational studies examining pre-, intra- and post-operative risk factors for POCD. A total of 330 papers were initially screened. Eleven meta-analyses were included in this umbrella review, which consisted of 73 risk factors in a total population of 67,622 participants. Most pertained to pre-operative risk factors (74%) that were predominantly examined using prospective designs and in cardiac-related surgeries (71%). Overall, 31 of the 73 factors (42%) were associated with a higher risk of POCD. However, there was no convincing (class I) or highly suggestive (class II) evidence for associations between risk factors and POCD, and suggestive evidence (class III) was limited to two risk factors (pre-operative age and pre-operative diabetes). Given that the overall strength of the evidence is limited, further large-scale studies that examine risk factors across various surgery types are recommended.

Mitigation of perioperative neurocognitive disorders: A holistic approach.

William Morton introduced the world to ether anesthesia for use during surgery in the Bullfinch Building of the Massachusetts General Hospital on October 16, 1846. For nearly two centuries, the prevailing wisdom had been that the effects of general anesthetics were rapidly and fully reversible, with no apparent long-term adverse sequelae. Despite occasional concerns of a possible association between surgery and anesthesia with dementia since 1887 (Savage, 1887), our initial belief was robustly punctured following the publication in 1998 of the International Study of Post-Operative Cognitive Dysfunction [ISPOCD 1] study by Moller et al. (1998) in The Lancet, in which they demonstrated in a prospective fashion that there were in fact persistent adverse effects on neurocognitive function up to 3 months following surgery and that these effects were common. Since the publication of that landmark study, significant strides have been made in redefining the terminology describing cognitive dysfunction, identifying those patients most at risk, and establishing the underlying etiology of the condition, particularly with respect to the relative contributions of anesthesia and surgery. In 2018, the International Nomenclature Consensus Working Group proposed new nomenclature to standardize identification of and classify perioperative cognitive changes under the umbrella of perioperative neurocognitive disorders (PND) (Evered et al., 2018a). Since then, the new nomenclature has tried to describe post-surgical cognitive derangements within a unifying framework and has brought to light the need to standardize methodology in clinical studies and motivate such studies with hypotheses of PND pathogenesis. In this narrative review, we highlight the relevant literature regarding recent key developments in PND identification and management throughout the perioperative period. We provide an overview of the new nomenclature and its implications for interpreting risk factors identified by clinical association studies. We then describe current hypotheses for PND development, using data from clinical association studies and neurophysiologic data where appropriate. Finally, we offer broad clinical guidelines for mitigating PND in the perioperative period, highlighting the role of Brain Enhanced Recovery After Surgery (Brain-ERAS) protocols.

Prolonged Unconsciousness is Common in COVID-19 and Associated with Hypoxemia.

OBJECTIVE: The purpose of this study was to estimate the time to recovery of command-following and associations between hypoxemia with time to recovery of command-following. METHODS: In this multicenter, retrospective, cohort study during the initial surge of the United States' pandemic (March-July 2020) we estimate the time from intubation to recovery of command-following, using Kaplan Meier cumulative-incidence curves and Cox proportional hazard models. Patients were included if they were admitted to 1 of 3 hospitals because of severe coronavirus disease 2019 (COVID-19), required endotracheal intubation for at least 7 days, and experienced impairment of consciousness (Glasgow Coma Scale motor score <6). RESULTS: Five hundred seventy-one patients of the 795 patients recovered command-following. The median time to recovery of command-following was 30 days (95% confidence interval [CI] = 27-32 days). Median time to recovery of command-following increased by 16 days for patients with at least one episode of an arterial partial pressure of oxygen (PaO2 ) value ≤55 mmHg (p < 0.001), and 25% recovered ≥10 days after cessation of mechanical ventilation. The time to recovery of command-following  was associated with hypoxemia (PaO2 ≤55 mmHg hazard ratio [HR] = 0.56, 95% CI = 0.46-0.68; PaO2 ≤70 HR = 0.88, 95% CI = 0.85-0.91), and each additional day of hypoxemia decreased the likelihood of recovery, accounting for confounders including sedation. These findings were confirmed among patients without any imagining evidence of structural brain injury (n = 199), and in a non-overlapping second surge cohort (N = 427, October 2020 to April 2021). INTERPRETATION: Survivors of severe COVID-19 commonly recover consciousness weeks after cessation of mechanical ventilation. Long recovery periods are associated with more severe hypoxemia. This relationship is not explained by sedation or brain injury identified on clinical imaging and should inform decisions about life-sustaining therapies. ANN NEUROL 2022;91:740-755.

Socioeconomic Disparities in Carotid Revascularization Procedures.

OBJECTIVES: Several studies have demonstrated healthcare disparities in postoperative outcomes after carotid endarterectomy and carotid artery stenting, including increased hospital mortality, postoperative stroke, and readmission rates. The objective of the present study was to examine the intersectionality between race/ethnicity, insurance status, and postoperative outcomes in carotid procedures. DESIGN: Records of adults from 2007 to 2014 were retrospectively identified, and patients with appropriate International Classification of Diseases Ninth Revision Clinical Modification codes for carotid endarterectomy or carotid artery stenting were identified. Primary outcomes were unadjusted rates and adjusted odds ratios (aORs) of postoperative in-hospital mortality, stroke, combined stroke/mortality, and cardiovascular complications. SETTING: Data were sourced from the State Inpatient Databases data from California, Florida, Kentucky, Maryland, and New York during the years 2007 to 2014. PARTICIPANTS: Patients undergoing carotid revascularization procedures. INTERVENTIONS: The effects of race and insurance status as independent variables and as effect modifiers on postoperative outcomes. MEASUREMENTS AND MAIN RESULTS: Multivariable logistic regression models were used to examine the associations between race and/or insurance status with respect to study outcomes. Race, but not payer status, was significantly associated with adverse outcomes after carotid artery procedures, with blacks, Hispanics, and other non-Caucasian races demonstrating a significantly greater risk of postoperative stroke and mortality (aOR range 1.24-1.59). This relationship persisted even when stratified by procedure type (aOR range 1.25-1.56) and symptomatology (aOR range 1.51-1.63). CONCLUSIONS: These results suggest that disparities in postoperative outcomes after carotid artery procedures are associated with race but not with primary insurance status. Multiple contributing factors exist, including racial inequities in prevalence of comorbidities, health literacy, and procedure type performed.

Optimizing Patient Access During an Emergency While Using Intraoperative Computed Tomography.

BACKGROUND: As minimally invasive spine surgery evolves, spine surgeons increasingly rely on advanced intraoperative computed tomography (iCT). iCT provides rapid acquisition of high-resolution images, reduces radiation exposure, improves surgical accuracy, and decreases operative time. However, all iCT systems currently available pose a patient safety risk as their physical space requirements limit patient access in the event of an emergency, particularly when patients are in the prone position. After a near-cardiac arrest at our institution during posterior cervical spine surgery, it was apparent that the presence of the iCT complicated the ability to rapidly reposition the patient in order to provide appropriate resuscitation. METHODS: To ensure our ability to provide timely care during an emergency, we determined that a process which included all members of the operating room (OR) team was required. We held an initial planning meeting where a detailed plan-of-action was created, reviewed, and revised in response to feedback from all stakeholders. We then simulated a cardiac arrest to test our resuscitation plan with all members of the neurosurgery team. A mannequin was positioned prone on an OR table within the iCT, and a resuscitation plan was created. RESULTS: The team orchestrated the mock resuscitation, and the time of cardiac arrest in the prone position to supine repositioning required 110 seconds. The simulation was recorded for post-"code" performance review. Application of the protocol during an actual cardiac arrest was associated with successful restoration of spontaneous circulation and full recovery. CONCLUSIONS: The development and rehearsal of an emergency plan of action greatly facilitated the timely responsiveness of the neurosurgical OR team during a simulated cardiac arrest and was an effective way to identify and address key logistical issues regarding the use of an iCT system.

An update on postoperative delirium: Clinical features, neuropathogenesis, and perioperative management.

Purpose of Review: We present a focused review on postoperative delirium for anesthesiologists, encompassing clinical features, neuropathogenesis, and clinical identification and management strategies based on risk factors and current delirium treatments. Recent Findings: The literature on postoperative delirium is dominated by non-experimental studies. We review delirium phenotypes, diagnostic criteria, and present standard nomenclature based on current literature. Disruption of cortical integration of complex information (CICI) may provide a framework to understand the neuropathogenesis of postoperative delirium, as well as risk factors and clinical modifiers in the perioperative period. We further divide risk factors into patient factors, surgical factors, and medical/pharmacological factors, and present specific considerations for each in the preoperative, intraoperative, and postoperative periods. Summary: Postoperative delirium is prevalent, poorly understood, and often missed with current screening techniques. Proper identification of risk factors is useful for perioperative interventions and can help tailor patient-specific management strategies.

The Role of Neuroinflammation in Postoperative Cognitive Dysfunction: Moving From Hypothesis to Treatment.

Postoperative cognitive dysfunction (POCD) is a common complication of the surgical experience and is common in the elderly and patients with preexisting neurocognitive disorders. Animal and human studies suggest that neuroinflammation from either surgery or anesthesia is a major contributor to the development of POCD. Moreover, a large and growing body of literature has focused on identifying potential risk factors for the development of POCD, as well as identifying candidate treatments based on the neuroinflammatory hypothesis. However, variability in animal models and clinical cohorts makes it difficult to interpret the results of such studies, and represents a barrier for the development of treatment options for POCD. Here, we present a broad topical review of the literature supporting the role of neuroinflammation in POCD. We provide an overview of the cellular and molecular mechanisms underlying the pathogenesis of POCD from pre-clinical and human studies. We offer a brief discussion of the ongoing debate on the root cause of POCD. We conclude with a list of current and hypothesized treatments for POCD, with a focus on recent and current human randomized clinical trials.

Effects of γ-Aminobutyric Acid Type A Receptor Modulation by Flumazenil on Emergence from General Anesthesia.

BACKGROUND: Transitions into conscious states are partially mediated by inactivation of sleep networks and activation of arousal networks. Pharmacologic hastening of emergence from general anesthesia has largely focused on activating subcortical monoaminergic networks, with little attention on antagonizing the γ-aminobutyric acid type A receptor (GABAAR). As the GABAAR mediates the clinical effects of many common general anesthetics, the authors hypothesized that negative GABAAR modulators would hasten emergence, possibly via cortical networks involved in sleep. METHODS: The authors investigated the capacity of the benzodiazepine rescue agent, flumazenil, which had been recently shown to promote wakefulness in hypersomnia patients, to alter emergence. Using an in vivo rodent model and an in vitro GABAAR heterologous expression system, they measured flumazenil's effects on behavioral, neurophysiologic, and electrophysiologic correlates of emergence from isoflurane anesthesia. RESULTS: Animals administered intravenous flumazenil (0.4 mg/kg, n = 8) exhibited hastened emergence compared to saline-treated animals (n = 8) at cessation of isoflurane anesthesia. Wake-like electroencephalographic patterns occurred sooner and exhibited more high-frequency electroencephalography power after flumazenil administration (median latency ± median absolute deviation: 290 ± 34 s) compared to saline administration (473 ± 186 s; P = 0.042). Moreover, in flumazenil-treated animals, there was a decreased impact on postanesthesia sleep. In vitro experiments in human embryonic kidney-293T cells demonstrated that flumazenil inhibited isoflurane-mediated GABA current enhancement (n = 34 cells, 88.7 ± 2.42% potentiation at 3 µM). Moreover, flumazenil exhibited weak agonist activity on the GABAAR (n = 10 cells, 10.3 ± 3.96% peak GABA EC20 current at 1 µM). CONCLUSIONS: Flumazenil can modulate emergence from isoflurane anesthesia. The authors highlight the complex role GABAARs play in mediating consciousness and provide mechanistic links between emergence from anesthesia and arousal.

Contribution of vision to postural behaviors during continuous support-surface translations.

During standing balance, kinematics of postural behaviors have been previously observed to change across visual conditions, perturbation amplitudes, or perturbation frequencies. However, experimental limitations only allowed for independent investigation of such parameters. Here, we adapted a pseudorandom ternary sequence (PRTS) perturbation previously used in rotational support-surface perturbations (Peterka in J Neurophysiol 88(3):1097-1118, 2002) to a translational paradigm, allowing us to concurrently examine the effects of vision, perturbation amplitude, and frequency on balance control. Additionally, the unpredictable PRTS perturbation eliminated effects of feedforward adaptations typical of responses to sinusoidal stimuli. The PRTS perturbation contained a wide spectral bandwidth (0.08-3.67 Hz) and was scaled to 4 different peak-to-peak amplitudes (3-24 cm). Root mean square (RMS) of hip displacement and velocity increased relative to RMS ankle displacement and velocity in the absence of vision across all subjects, especially at higher perturbation amplitudes. Gain and phase lag of center of mass (CoM) sway relative to the perturbation also increased with perturbation frequency; phase lag further increased when vision was absent. Together, our results suggest that visual input, perturbation amplitude, and perturbation frequency can concurrently and independently modulate postural strategies during standing balance. Moreover, each factor contributes to the difficulty of maintaining postural stability; increased difficulty evokes a greater reliance on hip motion. Finally, despite high degrees of joint angle variation across subjects, CoM measures were relatively similar across subjects, suggesting that the CoM is an important controlled variable for balance.

Long-latency muscle activity reflects continuous, delayed sensorimotor feedback of task-level and not joint-level error.

In both the upper and lower limbs, evidence suggests that short-latency electromyographic (EMG) responses to mechanical perturbations are modulated based on muscle stretch or joint motion, whereas long-latency responses are modulated based on attainment of task-level goals, e.g., desired direction of limb movement. We hypothesized that long-latency responses are modulated continuously by task-level error feedback. Previously, we identified an error-based sensorimotor feedback transformation that describes the time course of EMG responses to ramp-and-hold perturbations during standing balance (Safavynia and Ting 2013; Welch and Ting 2008, 2009). Here, our goals were 1) to test the robustness of the sensorimotor transformation over a richer set of perturbation conditions and postural states; and 2) to explicitly test whether the sensorimotor transformation is based on task-level vs. joint-level error. We developed novel perturbation trains of acceleration pulses such that perturbations were applied when the body deviated from the desired, upright state while recovering from preceding perturbations. The entire time course of EMG responses (∼4 s) in an antagonistic muscle pair was reconstructed using a weighted sum of center of mass (CoM) kinematics preceding EMGs at long-latency delays (∼100 ms). Furthermore, CoM and joint kinematic trajectories became decorrelated during perturbation trains, allowing us to explicitly compare task-level vs. joint feedback in the same experimental condition. Reconstruction of EMGs was poorer using joint kinematics compared with CoM kinematics and required unphysiologically short (∼10 ms) delays. Thus continuous, long-latency feedback of task-level variables may be a common mechanism regulating long-latency responses in the upper and lower limbs.

Sensorimotor feedback based on task-relevant error robustly predicts temporal recruitment and multidirectional tuning of muscle synergies.

We hypothesized that motor outputs are hierarchically organized such that descending temporal commands based on desired task-level goals flexibly recruit muscle synergies that specify the spatial patterns of muscle coordination that allow the task to be achieved. According to this hypothesis, it should be possible to predict the patterns of muscle synergy recruitment based on task-level goals. We demonstrated that the temporal recruitment of muscle synergies during standing balance control was robustly predicted across multiple perturbation directions based on delayed sensorimotor feedback of center of mass (CoM) kinematics (displacement, velocity, and acceleration). The modulation of a muscle synergy's recruitment amplitude across perturbation directions was predicted by the projection of CoM kinematic variables along the preferred tuning direction(s), generating cosine tuning functions. Moreover, these findings were robust in biphasic perturbations that initially imposed a perturbation in the sagittal plane and then, before sagittal balance was recovered, perturbed the body in multiple directions. Therefore, biphasic perturbations caused the initial state of the CoM to differ from the desired state, and muscle synergy recruitment was predicted based on the error between the actual and desired upright state of the CoM. These results demonstrate that that temporal motor commands to muscle synergies reflect task-relevant error as opposed to sensory inflow. The proposed hierarchical framework may represent a common principle of motor control across motor tasks and levels of the nervous system, allowing motor intentions to be transformed into motor actions.

Review and perspective: neuromechanical considerations for predicting muscle activation patterns for movement.

Muscle coordination may be difficult or impossible to predict accurately based on biomechanical considerations alone because of redundancy in the musculoskeletal system. Because many solutions exist for any given movement, the role of the nervous system in further constraining muscle coordination patterns for movement must be considered in both healthy and impaired motor control. On the basis of computational neuromechanical analyses of experimental data combined with modeling techniques, we have demonstrated several such neural constraints on the temporal and spatial patterns of muscle activity during both locomotion and postural responses to balance perturbations. We hypothesize that subject-specific and trial-by-trial differences in muscle activation can be parameterized and understood by a hierarchical and low-dimensional framework that reflects the neural control of task-level goals. In postural control, we demonstrate that temporal patterns of muscle activity may be governed by feedback control of task-level variables that represent the overall goal-directed motion of the body. These temporal patterns then recruit spatially-fixed patterns of muscle activity called muscle synergies that produce the desired task-level biomechanical functions that require multijoint coordination. Moreover, these principles apply more generally to movement, and in particular to locomotor tasks in both healthy and impaired individuals. Overall, understanding the goals and organization of the neural control of movement may provide useful reduced dimension parameter sets to address the degrees-of-freedom problem in musculoskeletal movement control. More importantly, however, neuromechanical analyses may lend insight and provide a framework for understanding subject-specific and trial-by-trial differences in movement across both healthy and motor-impaired populations.

Herbal, vitamin, and mineral supplement use in patients enrolled in a cardiac rehabilitation program.

PURPOSE: The use of complementary and alternative medicine is common and continues to rise each year, both in the general population and among those with cardiovascular disease. While some supplements may incur risk, particularly when used concomitantly with cardiovascular medications, others have proven benefits. However, supplements such as antioxidants and many herbs can have significant interactions with cardiovascular medications. This study aimed to identify the percentage of patients enrolled in a cardiac rehabilitation program taking herbal, vitamin, and mineral supplements. METHODS: Electronic and paper charts of 235 patients enrolled in a phase 3 cardiac rehabilitation program were reviewed. Their demographics, medical history, and medications were stratified in an Excel chart, using a large matrix from which data were imported into Matlab for analysis. Custom Matlab programs were created and compiled to determine variables of interest, including percentages of patients with a specific medical condition taking certain supplements. RESULTS: Sixty-seven percent of patients enrolled in the cardiac rehabilitation program were taking vitamins, with or without minerals (67%, 158 of 235). Multivitamin is the most common form of supplement (51%, 119 of 235), followed by fish oil/omega-3 polyunsaturated fatty acids (27%, 64 of 235). CONCLUSION: The majority of patients in a phase 3 cardiac rehabilitation program are taking some form of herbal, vitamin, or mineral supplement. Given frequent, complicated patient medication regimens, it is important to educate patients on the potential benefits as well as lack of evidence and possible dangers of supplements.

Task-level feedback can explain temporal recruitment of spatially fixed muscle synergies throughout postural perturbations.

Recent evidence suggests that complex spatiotemporal patterns of muscle activity can be explained with a low-dimensional set of muscle synergies or M-modes. While it is clear that both spatial and temporal aspects of muscle coordination may be low dimensional, constraints on spatial versus temporal features of muscle coordination likely involve different neural control mechanisms. We hypothesized that the low-dimensional spatial and temporal features of muscle coordination are independent of each other. We further hypothesized that in reactive feedback tasks, spatially fixed muscle coordination patterns-or muscle synergies-are hierarchically recruited via time-varying neural commands based on delayed task-level feedback. We explicitly compared the ability of spatially fixed (SF) versus temporally fixed (TF) muscle synergies to reconstruct the entire time course of muscle activity during postural responses to anterior-posterior support-surface translations. While both SF and TF muscle synergies could account for EMG variability in a postural task, SF muscle synergies produced more consistent and physiologically interpretable results than TF muscle synergies during postural responses to perturbations. Moreover, a majority of SF muscle synergies were consistent in structure when extracted from epochs throughout postural responses. Temporal patterns of SF muscle synergy recruitment were well-reconstructed by delayed feedback of center of mass (CoM) kinematics and reproduced EMG activity of multiple muscles. Consistent with the idea that independent and hierarchical low-dimensional neural control structures define spatial and temporal patterns of muscle activity, our results suggest that CoM kinematics are a task variable used to recruit SF muscle synergies for feedback control of balance.

Muscle Synergies: Implications for Clinical Evaluation and Rehabilitation of Movement.

We present a method called muscle synergy analysis, which can offer clinicians insight into both underlying neural strategies for movement and functional outcomes of muscle activity. Although neural dysfunction is central to many motor deficits, neural activity during movements is not directly measurable. Consequently, the majority of clinical tests focus on evaluating motor outputs at the behavioral and kinematic levels. However, altered behavioral or kinematic outcomes could be the result of multiple distinct neural abnormalities with very different muscle coordination patterns. Because muscle activity reflects motoneuron activity and generates the forces that produce behavioral outcomes, an analysis of muscle activity may provide a better understanding of the functional neural deficits in the impaired nervous system. Unfortunately electromyographic datasets can be large, highly variable, and difficult to interpret, precluding their clinical utility. Computational analyses can be used to extract muscle synergies from such datasets, revealing underlying patterns that may reflect different levels of neural function. These muscle synergies are hypothesized to represent motor modules recruited by the nervous system to flexibly perform biomechanical subtasks necessary for movement. For example, hemiparetic stroke patients exhibit differences in the number of muscle synergies, which may reflect disruptions in descending neural pathways and are correlated to deficits in motor function. Muscle synergy analysis may thus offer the clinician a better view of the neural structure underlying motor behaviors and how they change in motor deficits and rehabilitation. Such information could inform diagnostic tools and evidence-based interventions specifically targeted to a patient's deficits.

Common muscle synergies for control of center of mass and force in nonstepping and stepping postural behaviors.

We investigated muscle activity, ground reaction forces, and center of mass (CoM) acceleration in two different postural behaviors for standing balance control in humans to determine whether common neural mechanisms are used in different postural tasks. We compared nonstepping responses, where the base of support is stationary and balance is recovered by returning CoM back to its initial position, with stepping responses, where the base of support is enlarged and balance is recovered by pushing the CoM away from the initial position. In response to perturbations of the same direction, these two postural behaviors resulted in different muscle activity and ground reaction forces. We hypothesized that a common pool of muscle synergies producing consistent task-level biomechanical functions is used to generate different postural behaviors. Two sets of support-surface translations in 12 horizontal-plane directions were presented, first to evoke stepping responses and then to evoke nonstepping responses. Electromyographs in 16 lower back and leg muscles of the stance leg were measured. Initially (∼100-ms latency), electromyographs, CoM acceleration, and forces were similar in nonstepping and stepping responses, but these diverged in later time periods (∼200 ms), when stepping occurred. We identified muscle synergies using non-negative matrix factorization and functional muscle synergies that quantified correlations between muscle synergy recruitment levels and biomechanical outputs. Functional muscle synergies that produce forces to restore CoM position in nonstepping responses were also used to displace the CoM during stepping responses. These results suggest that muscle synergies represent common neural mechanisms for CoM movement control under different dynamic conditions: stepping and nonstepping postural responses.