Phillip E. Vlisides

Intraoperative ketamine for prevention of postoperative delirium or pain after major surgery in older adults: an international, multicentre, double-blind, randomised clinical trial

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 to ketamine and postoperative analgesia, the unexpected secondary findings regarding pain and opioid consumption warrant replication or refutation in subsequent research. Funding The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The principal investigators (MSA and GAM) had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Ketamine: 50 years of modulating the mind

Ketamine was introduced into clinical practice in the 1960s and continues to be both clinically useful and scientifically fascinating. With considerably diverse molecular targets and neurophysiological properties, ketamine’s effects on the central nervous system remain incompletely understood. Investigators have leveraged the unique characteristics of ketamine to explore the invariant, fundamental mechanisms of anesthetic action. Emerging evidence indicates that ketamine-mediated anesthesia may occur via disruption of corticocortical information transfer in a frontal-to-parietal (“top down”) distribution. This proposed mechanism of general anesthesia has since been demonstrated with anesthetics in other pharmacological classes as well. Ketamine remains invaluable to the fields of anesthesiology and critical care medicine, in large part due to its ability to maintain cardiorespiratory stability while providing effective sedation and analgesia. Furthermore, there may be an emerging role for ketamine in treatment of refractory depression and Post-Traumatic Stress Disorder. In this article, we review the history of ketamine, its pharmacology, putative mechanisms of action and current clinical applications.

Incidence of Connected Consciousness after Tracheal Intubation: A Prospective, International, Multicenter Cohort Study of the Isolated Forearm Technique.

Background: The isolated forearm technique allows assessment of consciousness of the external world (connected consciousness) through a verbal command to move the hand (of a tourniquet-isolated arm) during intended general anesthesia. Previous isolated forearm technique data suggest that the incidence of connected consciousness may approach 37% after a noxious stimulus. The authors conducted an international, multicenter, pragmatic study to establish the incidence of isolated forearm technique responsiveness after intubation in routine practice. Methods: Two hundred sixty adult patients were recruited at six sites into a prospective cohort study of the isolated forearm technique after intubation. Demographic, anesthetic, and intubation data, plus postoperative questionnaires, were collected. Univariate statistics, followed by bivariate logistic regression models for age plus variable, were conducted. Results: The incidence of isolated forearm technique responsiveness after intubation was 4.6% (12/260); 5 of 12 responders reported pain through a second hand squeeze. Responders were younger than nonresponders (39 ± 17 vs. 51 ± 16 yr old; P = 0.01) with more frequent signs of sympathetic activation (50% vs. 2.4%; P = 0.03). No participant had explicit recall of intraoperative events when questioned after surgery (n = 253). Across groups, depth of anesthesia monitoring values showed a wide range; however, values were higher for responders before (54 ± 20 vs. 42 ± 14; P = 0.02) and after (52 ± 16 vs. 43 ± 16; P = 0.02) intubation. In patients not receiving total intravenous anesthesia, exposure to volatile anesthetics before intubation reduced the odds of responding (odds ratio, 0.2 [0.1 to 0.8]; P = 0.02) after adjustment for age. Conclusions: Intraoperative connected consciousness occurred frequently, although the rate is up to 10-times lower than anticipated. This should be considered a conservative estimate of intraoperative connected consciousness.

Neurophysiologic Correlates of Ketamine Sedation and Anesthesia: A High-density Electroencephalography Study in Healthy Volunteers

Background: Previous studies have demonstrated inconsistent neurophysiologic effects of ketamine, although discrepant findings might relate to differences in doses studied, brain regions analyzed, coadministration of other anesthetic medications, and resolution of the electroencephalograph. The objective of this study was to characterize the dose-dependent effects of ketamine on cortical oscillations and functional connectivity. Methods: Ten healthy human volunteers were recruited for study participation. The data were recorded using a 128-channel electroencephalograph during baseline consciousness, subanesthetic dosing (0.5 mg/kg over 40 min), anesthetic dosing (1.5 mg/kg bolus), and recovery. No other sedative or anesthetic medications were administered. Spectrograms, topomaps, and functional connectivity (weighted and directed phase lag index) were computed and analyzed. Results: Frontal theta bandwidth power increased most dramatically during ketamine anesthesia (mean power ± SD, 4.25 ± 1.90 dB) compared to the baseline (0.64 ± 0.28 dB), subanesthetic (0.60 ± 0.30 dB), and recovery (0.68 ± 0.41 dB) states; P < 0.001. Gamma power also increased during ketamine anesthesia. Weighted phase lag index demonstrated theta phase locking within anterior regions (0.2349 ± 0.1170, P < 0.001) and between anterior and posterior regions (0.2159 ± 0.1538, P < 0.01) during ketamine anesthesia. Alpha power gradually decreased with subanesthetic ketamine, and anterior-to-posterior directed connectivity was maximally reduced (0.0282 ± 0.0772) during ketamine anesthesia compared to all other states (P < 0.05). Conclusions: Ketamine anesthesia correlates most clearly with distinct changes in the theta bandwidth, including increased power and functional connectivity. Anterior-to-posterior connectivity in the alpha bandwidth becomes maximally depressed with anesthetic ketamine administration, suggesting a dose-dependent effect.

Estimating the Integrated Information Measure Phi from High-Density Electroencephalography during States of Consciousness in Humans

The integrated information theory (IIT) proposes a quantitative measure, denoted as Φ, of the amount of integrated information in a physical system, which is postulated to have an identity relationship with consciousness. IIT predicts that the value of Φ estimated from brain activities represents the level of consciousness across phylogeny and functional states. Practical limitations, such as the explosive computational demands required to estimate Φ for real systems, have hindered its application to the brain and raised questions about the utility of IIT in general. To achieve practical relevance for studying the human brain, it will be beneficial to establish the reliable estimation of Φ from multichannel electroencephalogram (EEG) and define the relationship of Φ to EEG properties conventionally used to define states of consciousness. In this study, we introduce a practical method to estimate Φ from high-density (128-channel) EEG and determine the contribution of each channel to Φ. We examine the correlation of power, frequency, functional connectivity, and modularity of EEG with regional Φ in various states of consciousness as modulated by diverse anesthetics. We find that our approximation of Φ alone is insufficient to discriminate certain states of anesthesia. However, a multi-dimensional parameter space extended by four parameters related to Φ and EEG connectivity is able to differentiate all states of consciousness. The association of Φ with EEG connectivity during clinically defined anesthetic states represents a new practical approach to the application of IIT, which may be used to characterize various physiological (sleep), pharmacological (anesthesia), and pathological (coma) states of consciousness in the human brain.

Subanaesthetic ketamine and altered states of consciousness in humans

Background Despite its designation as a ‘dissociative anaesthetic,’ the dissociative and psychoactive effects of ketamine remain incompletely understood. The goal of this study was to characterise the subjective experiences and accompanying EEG changes with subanaesthetic doses of ketamine. Methods High‐density EEG was recorded in 15 human volunteers before, during, and after subanaesthetic ketamine infusion (0.5 mg kg−1 over 40 min), with self‐reported measures of altered states of consciousness obtained after ketamine exposure. Sensor‐ and source‐level EEG changes were analysed with a focus on spectral power and regional changes. Results Ketamine‐induced altered states were characterised predominantly by dissociative experiences such as disembodiment and ego transcendence; sensory disturbances were also common. Ketamine broadly decreased low‐frequency power, with mean reductions largest at alpha (8–12 Hz) in parietal (−0.94 dB, P<0.001) and occipital (−1.8 dB, P<0.001) channel clusters. Significant decreases in alpha were identified in the precuneus and temporal‐parietal junction. Conclusions Ketamine induces altered states of consciousness during periods of reduced alpha power in the precuneus and temporal‐parietal junction. Modulation of these temporal‐parietal loci are candidate mechanisms of the psychoactive effects of ketamine, given that this region is involved in multisensory integration, body representation, and consciousness.

Clinical Application of Raw and Processed EEG

Although the human electroencephalogram (EEG) was first reported in the 1920s and first proposed as an intraoperative monitor in the 1930s, only in the past few decades has the EEG received focused attention in the field of anesthesiology. The evolution of EEG in the perioperative period has occurred in three stages. First, there was an exploration of raw EEG, which proved impractical given cumbersome machines, paper records, and the lack of an invariant EEG signature for general anesthesia. Second, there was a focus on processed EEG monitors, which were practical and convenient through the display of a single index but whose neuroscientific validity and broad utility is still in question. Most recently, there have been more principled approaches to understanding the EEG during anesthesia that are based either on mechanisms of general anesthetics or mechanisms of consciousness. Originally developed to assess depth of anesthesia, processed EEG monitoring has not consistently been shown to reduce the incidence of awareness under anesthesia in comparison to alarms based on minimum alveolar concentration. It has also been suggested that EEG-guided titration of anesthetics may improve cognitive function after surgery by avoiding anesthetic overdose, but more definitive studies are needed. In this chapter, we review the basics of EEG acquisition and interpretation, the neurophysiologic properties of anesthetics, and the clinical utility of raw and processed EEG in various settings.

Reconceptualising stroke research to inform the question of anaesthetic neurotoxicity

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Brain imaging reveals covert consciousness during behavioral unresponsiveness induced by propofol

Detecting covert consciousness in behaviorally unresponsive patients by brain imaging is of great interest, but a reproducible model and evidence from independent sources is still lacking. Here we demonstrate the possibility of using general anesthetics in a within-subjects study design to test methods or statistical paradigms of assessing covert consciousness. Using noninvasive neuroimaging in healthy volunteers, we identified a healthy study participant who was able to exhibit the specific fMRI signatures of volitional mental imagery while behaviorally unresponsive due to sedation with propofol. Our findings reveal a novel model that may accelerate the development of new approaches to reproducibly detect covert consciousness, which is difficult to achieve in patients with heterogeneous and sometimes clinically unstable neuropathology.

Intraoperative ketamine for prevention of depressive symptoms after major surgery in older adults: an international, multicentre, double-blind, randomised clinical trial

Background: Ketamine is a general anaesthetic with anti‐depressant effects at subanaesthetic doses. We hypothesised that intraoperative administration of ketamine would prevent or mitigate postoperative depressive symptoms in surgical patients. Methods: We conducted an international, randomised clinical trial testing the effects of intraoperative administration of ketamine [0.5 mg kg−1 (Lo‐K) or 1.0 mg kg−1 (Hi‐K)] vs control [saline placebo (P)] in patients ≥60 yr old undergoing major surgery with general anaesthesia. We administered the Patient Health Questionnaire‐8 before the operation, on postoperative day (POD) 3 (primary outcome), and on POD30 to assess depressive symptoms, a secondary outcome of the original trial. Results: There was no significant difference on POD3 in the proportion of patients with symptoms suggestive of depression between the placebo [23/156 (14.7%)] and combined ketamine (Lo‐K plus Hi‐K) [61/349 (17.5%)] groups [difference = –2.7%; 95% confidence interval (CI), 5.0% to –9.4%; P=0.446]. Of the total cohort, 9.6% (64/670; 95% CI, 7.6–12.0%) had symptoms suggestive of depression before operation, which increased to 16.6% (84/505; 95% CI, 13.6–20.1%) on POD3, and decreased to 11.9% (47/395; 95% CI, 9.1–15.5%) on POD30. Of the patients with depressive symptoms on POD3 and POD30, 51% and 49%, respectively, had no prior history of depression or depressive symptoms. Conclusions: Major surgery is associated with new‐onset symptoms suggestive of depression in patients ≥60 yr old. Intraoperative administration of subanaesthetic ketamine does not appear to prevent or improve depressive symptoms. Clinical trials registration: NCT01690988.