929 Neural Correlates of Wakefulness, Sleep, and General Anesthesia: An Experimental Study in Rat
The relationship of cortical acetylcholine and electroencephalographic (EEG) indices of corticocortical connectivity—coherence and symbolic transfer entropy—was studied in rats before, during, and after propofol- and sevoflurane-induced unconsciousness. These EEG indices were also analyzed during wakefulness, slow wave sleep (SWS), and rapid eye movement (REM) sleep in other rats. EEG coherence and frontal-parietal directed connectivity in the high gamma (85 to 155 Hz) bandwidth were present during wakefulness and were disrupted during physiological (SWS and REM sleep) and pharmacological (propofol and sevoflurane) states of unconsciousness. Coherence and bidirectional frontal-parietal connectivity in the theta (4 to 10 Hz) bandwidth were present during states of cortical activation (low amplitude—fast wave electroencephalogram) with (wakefulness) or without (REM sleep) behavioral arousal, and correlated with cortical acetylcholine concentrations. Coherence and frontal-parietal directed connectivity in high gamma band were not mediated by cholinergic mechanisms. See the accompanying Editorial View on page 832.
861 Neural Correlates of Sevoflurane-induced Unconsciousness Identified by Simultaneous Functional Magnetic Resonance Imaging and Electroencephalography
Resting-state functional magnetic resonance imaging (fMRI) and electroencephalography were recorded simultaneously in 16 volunteers while awake and during sevoflurane anesthesia at burst suppression, 3 vol% and suppression and 3 and 2 vol% steady-state concentrations to test the hypothesis that, like propofol, sevoflurane would reduce frontal information processing (measured by permutation entropy [PEn]) and disrupt frontoparietal connectivity, resulting in decreased frontal-to-parietal directed connectivity (DC, measured by symbolic transfer entropy [STEn]). Sevoflurane at 2 and 3 vol% profoundly decreased fMRI-based measures of functional connectivity in frontal networks, especially ventral parts of the frontoparietal attention networks. Thalamocortical functional connectivity was decreased in all stages of anesthesia. Electroencephalographic analyses findings of a pronounced decrease in surrogates of information processing (PEn) in the frontal cortex and reversal of DC (STEn) between frontoparietal electrode pairs were consistent with those of fMRI. See the accompanying Editorial View on page 827.
873 Resting-state Network-specific Breakdown of Functional Connectivity during Ketamine Alteration of Consciousness in Volunteers
The hypnotic effects of ketamine are largely mediated by blockade of N-methyl-D-aspartate receptors and HCN1 channels. A functional magnetic resonance imaging study was conducted in eight volunteers submitted to stepwise increments in plasma ketamine concentrations, up to loss of responsiveness to verbal command, to explore the effects of ketamine on within and between resting-state consciousness networks connectivities. Ketamine-induced unresponsiveness has features in common with that induced by GABA ergic drugs, including breakdown of frontal-parietal connectivity and of anticorrelated activity between the Default-Mode network (DMn) and other brain regions. Ketamine preserved subcortical input to the cortex in addition to sensory and motor processing. Alteration of higher-order integration networks (such as the DMn) and their anticorrelation with other networks as well as breakdown of Salience network connectivity are responsible for mental content perturbation under ketamine sedation. See the accompanying Editorial View on page 830.
952 Exposure of Stored Packed Erythrocytes to Nitric Oxide Prevents Transfusion-associated Pulmonary Hypertension
The viability of erythrocytes is reduced by extended storage, leading to release of hemoglobin into the red blood cell (RBC) unit supernatant. Circulating cell-free hemoglobin and hemoglobin-containing microvesicles scavenge nitric oxide generated by endothelial cells, which may be the cause of pulmonary vasoconstriction after transfusion of stored blood. Nitric oxide consumption by ovine RBC supernatant fluid was reduced when stored RBC units were treated with either nitric oxide gas or a short-lived nitric oxide donor, due to conversion of extracellular oxyhemoglobin to methemoglobin, which is unable to scavenge nitric oxide. Nitric oxide treatment of stored RBCs by either method prevented pulmonary vasoconstriction and hypertension in lambs during and after transfusion of autologous erythrocytes stored for either 2 days or 40 days. Washing stored RBCs before transfusion did not prevent pulmonary hypertension.
889 Distinct Cortical Signatures Associated with Sedation and Respiratory Rate Depression by Morphine in a Pediatric Population
An observational study was conducted in pediatric patients to identify cortical signatures of morphine-induced sedation and to determine how these are associated with respiratory changes. The effect of morphine on cortical activity, as measured by electroencephalogram spectral content, topography, and coherence, was determined in young patients given morphine for pain relief after elective surgery as were its effects on respiratory activity. Morphine reduced high-frequency (β1 and β2 band powers, 13.5 to 30 Hz) cortical activity in the central and frontal lobes, without changing low-frequency activity or affecting occipital lobe activities. These results were characteristic of morphine-induced sedation and distinct from the changes induced by non–rapid eye movement sleep. Morphine decreased frontal-occipital coherence in the β2 electroencephalographic frequency band. Morphine-induced changes in respiratory rate were related to the reduction in β1 frequency cortical activity and frontal-occipital coherence.
992 Lung Metabolic Activation as an Early Biomarker of Acute Respiratory Distress Syndrome and Local Gene Expression Heterogeneity
Acute respiratory distress syndrome (ARDS) is conceived to be an acute, diffuse, inflammatory lung injury with increased pulmonary vascular permeability and lung density. The hypothesis that lung cellular metabolism and gene expression manifest spatial and temporal heterogeneity in response to distinct regional injury mechanisms and precede density changes detectable with conventional radiography was tested in sheep subjected to endotoxemia and mechanical ventilation over 20 h, which reprises the “two-hit’’ injury often seen in patients. Multitracer positron emission tomography and gene expression techniques were used to study molecular processes during early ARDS development. Increased in vivo whole-lung and regional metabolic activation were observed within the first 20 h of lung injury, which preceded lung density increases used routinely for ARDS diagnosis. Temporal trajectories of metabolic activation were spatially heterogeneous and co-registered with topographical heterogeneity in gene expression. See the accompanying Editorial View on page 838.
1046 Association between Participation in an Intensive Longitudinal Assessment Program and Performance on a Cognitive Examination in the Maintenance of Certification in Anesthesiology Program®
The American Board of Anesthesiology (ABA) requires diplomates with time-limited certificates to participate in a Maintenance of Certification in Anesthesiology Program® (MOCA®). The Assessment of Knowledge, Judgment, and Skills by the MOCA Cognitive Examination has to be passed every ten years. The ABA launched the pilot MOCA Minute program, a web-based longitudinal assessment involving weekly questions with immediate feedback and links to learning resources, in 2014 to help diplomates master topics included in the Cognitive Examination. The hypothesis that voluntary enrollment and participation in the MOCA Minute program is associated with improved performance on the Cognitive Examination was tested in an observational study. When other factors were taken into account, participation in MOCA Minute was associated with a modest but significant improvement in performance for items querying topics covered by MOCA Minute questions and those in other topic areas. See the accompanying Editorial View on page 844.
846 Preclinical Pain Research: Can We Do Better?
The ability of modern medicine to control both acute and chronic pain is limited despite extensive pain research. Clinical trials of newly designed drugs that were effective in changing pain-related behavior in preclinical models have often failed. This special article reviews reasons for these failures and makes recommendations for how to improve the process. Reasons for failure include poor preclinical pain models, preclinical pain measures, and reporting practices. Recommendations include selecting models closely resembling their targeted clinical conditions, studying animals under conditions relevant to clinical pain, and using pain measures involving more informative behaviors as alternatives to, or in addition to, evoked responses largely involving spinal reflexes. A final recommendation is that reports should be written clearly and accurately, key experimental details should be included, and sources of potential bias should be disclosed.