Introduction Directional connectivity from anterior to posterior brain regions (or “feedback” connectivity) has been shown to be inhibited by the gamma-aminobutyric acid agonists propofol and sevoflurane. In this study we tested the hypothesis that ketamine would also inhibit cortical feedback connectivity in frontoparietal networks. Methods Surgical patients (n=30) were recruited for induction of anesthesia with intravenous ketamine (2mg/kg); electroencephalography of the frontal and parietal regions was acquired. We used normalized symbolic transfer entropy, a computational method based in information theory, to measure directional connectivity across frontal and parietal regions. Statistical analysis of transfer entropy measures was performed with the permutation test and the time shift test to exclude false positive connectivity. For comparison, we used normalized symbolic transfer entropy to reanalyze electroencephalographic data gathered from surgical patients receiving either propofol (n=9) or sevoflurane (n=9) for anesthetic induction. Results Ketamine reduced alpha power and increased gamma power, in contrast to both propofol and sevoflurane. During administration of ketamine, feedback connectivity gradually diminished and was significantly inhibited after loss of consciousness (Mean±SD of baseline & anesthesia: 0.0074±0.003 & 0.0055±0.0027, F(5,179)= 7.785, p<0.0001). By contrast, feedforward connectivity was preserved during exposure to ketamine (Mean±SD of baseline & anesthesia: 0.0041±0.0015 & 0.0046±0.0018, F(5,179)=2.07, p=0.072). Like ketamine, propofol and sevoflurane selectively inhibited feedback connectivity after anesthetic induction. Conclusions Three major classes of anesthetics disrupt frontal-parietal communication, despite molecular and neurophysiologic differences. Analysis of directional connectivity in frontal-parietal networks could provide a common metric of general anesthesia and insight into the cognitive neuroscience of anesthetic-induced unconsciousness.

Background Delirium and pain are common and serious postoperative complications. Subanaesthetic ketamine is often administered intraoperatively for postoperative analgesia and to spare postoperative opioids. Some evidence also suggests that ketamine prevents delirium. The primary purpose of this trial was to evaluate the effectiveness of ketamine in preventing postoperative delirium in older adults after major surgery. Secondary outcomes, viewed as strongly related to delirium, were postoperative pain and opioid consumption. Methods This was a multicentre, international, randomised trial that enrolled adults older than 60 undergoing major cardiac and noncardiac surgery under general anaesthesia. Participants were enrolled prior to surgery and gave written informed consent. We used a computer-generated randomisation sequence. Patients at study sites were randomised to one of three study groups in blocks of 15 to receive intraoperative administration of (i) placebo (intravenous normal saline), (ii) low dose ketamine (0.5 mg/kg) or (iii) high dose ketamine (1 mg/kg). Study drug was administered following induction of anaesthesia, prior to surgical incision. Participants, clinicians, and investigators were all masked to group assignment. Delirium and pain were assessed twice daily in the first three postoperative days using the Confusion Assessment Method and Visual Analog Scale, respectively. Postoperative opioid use was recorded, and hallucinations and nightmares were assessed. Analyses were performed by intention-to-treat and adverse events were evaluated. The Prevention of Delirium and Complications Associated with Surgical Treatments [PODCAST] trial is registered in clinicaltrials.gov; NCT01690988 Findings Between February 6, 2014 and June 26, 2016, 1360 patients assessed and 672 were randomised, with 222 in the placebo group, 227 in the low dose ketamine group, and 223 in the high dose ketamine group. There was no difference in postoperative delirium incidence between those in the combined ketamine groups and those who received placebo (19.45% vs. 19.82%, respectively; absolute difference, 0.36%; 95% CI, −6.07% to 7.38%; p=0.92). There were no significant differences among the three groups in maximum pain scores (p=0.88) or median opioid consumption (p=0.47) over time. There were more postoperative hallucinations (p=0.01) and nightmares (p=0.03) with escalating doses of ketamine. Adverse events (cardiovascular, renal, infectious, gastrointestinal, bleeding), whether viewed individually (P value for each >0.40) or collectively (82/222 [36.9%] in placebo group, 90/227 [39.6%] in low dose ketamine group, 91/223 in high dose ketamine group [40.8%]; P=0.69), did not differ significantly across the three groups. Interpretation The administration of a single subanaesthetic dose of ketamine to older adults during major surgery did not show evidence of reducing postoperative delirium, pain, or opioid consumption, and might cause harm by inducing negative experiences. Given current evidence and guidelines related...

BackgroundThe precise mechanism and optimal measure of anesthetic-induced unconsciousness has yet to be elucidated. Preferential inhibition of feedback connectivity from frontal to parietal brain networks is one potential neurophysiologic correlate, but has only been demonstrated in animals or under limited conditions in healthy volunteers.Methods and FindingsWe recruited eighteen patients presenting for surgery under general anesthesia; electroencephalography of the frontal and parietal regions was acquired during (i) baseline consciousness, (ii) anesthetic induction with propofol or sevoflurane, (iii) general anesthesia, (iv) recovery of consciousness, and (v) post-recovery states. We used two measures of effective connectivity, evolutional map approach and symbolic transfer entropy, to analyze causal interactions of the frontal and parietal regions. The dominant feedback connectivity of the baseline conscious state was inhibited after anesthetic induction and during general anesthesia, resulting in reduced asymmetry of feedback and feedforward connections in the frontoparietal network. Dominant feedback connectivity returned when patients recovered from anesthesia. Both analytic techniques and both classes of anesthetics demonstrated similar results in this heterogeneous population of surgical patients.ConclusionsThe disruption of dominant feedback connectivity in the frontoparietal network is a common neurophysiologic correlate of general anesthesia across two anesthetic classes and two analytic measures. This study represents a key translational step from the underlying cognitive neuroscience of consciousness to more sophisticated monitoring of anesthetic effects in human surgical patients.