Delirium Predicts Three-Month Mortality in Critically Ill Patients: A New Model

Delirium is a neurocognitive disorder defined as an acute disturbance in attention, awareness, and cognition with a fluctuating course not better explained by a preexisting condition (American Psychiatric Association, 2013). It is prevalent in up to 70% of hospital patients and 82% of patients in the intensive care unit (ICU; Ely, Speroff, Gordon, & Bernard, 2004; Kavanagh & Gottfried, 2007; Mcnicoll, Pisani, Ely, Gifford, & Inouye, 2005). The impact of delirium on mortality is inconsistent in the literature. Many studies have concluded that delirium prevalence is associated with increased risk of mortality (Cole, 2004; Kavanagh & Gottfried, 2007; Moskowitz et al., 2017; Pandharipande et al., 2013; Pauley et al., 2015), while others suggest delirium does not increase risk of patients dying (Levkoff et al., 1992; Wolters et al., 2014). The objective of this retrospective observational study was to determine if delirium is an independent predictor of mortality and develop a new model predicting three-month mortality of critically ill patients. Of the 165 patients followed in this study, 42 (25.5%) were deceased at three months and 123 (74.5%) survived. The most accurate model of predicting three-month mortality had an area under the curve of 0.89 (CI: 0.81 to 0.94), which included delirium burden defined as the fraction of the number of days patients were positive for individual features of delirium during their hospital stay. The main finding of the present study is the development of a new model that accurately predicts three-month mortality of critically ill patients. This study provides further evidence that delirium is an independent predictor of mortality and new evidence that delirium fraction improves the accuracy of a predictive models of mortality. We also identified individual features of delirium that are more predictive of mortality than others. Future research is needed to develop prevention measures and treatment interventions for delirium in the ICU and on hospital floors to reduce risk of patient mortality

Electrophysiological indices of aesthetically stimulated processes in art-experienced individuals as compared to art-naïve individuals

Aesthetic judgment processes were investigated in art-experienced and art-naïve individuals. Previous electrophysiological data suggest that aesthetic judgment is a two-stage process (Hofel & Jacobson, 2007). The first stage of aesthetic judgment is impression formation which is not spontaneous, and is reflected by an early Event Related Potential (ERP) frontocentral deflection. The second stage reflected by a lateralized late ERP positivity, evaluative categorization is also not spontaneous. Participants in the current study were instructed to either simply view black and white geometric patterns or were instructed to contemplate the beauty of the patterns. Results suggest that aesthetically stimulated processes differ between art-expereinced individuals and art-naive individuals, and impression formation requires intention in art-naive individuals, but occurs spontaneously in art-experienced individuals

Electrophysiological indices of aesthetically stimulated processes in art-experienced individuals as compared to art-naïve individuals

Aesthetic judgment processes were investigated in art-experienced and art-naïve individuals. Previous electrophysiological data suggest that aesthetic judgment is a two-stage process (Hofel & Jacobson, 2007). The first stage of aesthetic judgment is impression formation which is not spontaneous, and is reflected by an early Event Related Potential (ERP) frontocentral deflection. The second stage reflected by a lateralized late ERP positivity, evaluative categorization is also not spontaneous. Participants in the current study were instructed to either simply view black and white geometric patterns or were instructed to contemplate the beauty of the patterns. Results suggest that aesthetically stimulated processes differ between art-expereinced individuals and art-naive individuals, and impression formation requires intention in art-naive individuals, but occurs spontaneously in art-experienced individuals

Delirium Predicts Three-Month Mortality in Critically Ill Patients: A New Model

Delirium is a neurocognitive disorder defined as an acute disturbance in attention, awareness, and cognition with a fluctuating course not better explained by a preexisting condition (American Psychiatric Association, 2013). It is prevalent in up to 70% of hospital patients and 82% of patients in the intensive care unit (ICU; Ely, Speroff, Gordon, & Bernard, 2004; Kavanagh & Gottfried, 2007; Mcnicoll, Pisani, Ely, Gifford, & Inouye, 2005). The impact of delirium on mortality is inconsistent in the literature. Many studies have concluded that delirium prevalence is associated with increased risk of mortality (Cole, 2004; Kavanagh & Gottfried, 2007; Moskowitz et al., 2017; Pandharipande et al., 2013; Pauley et al., 2015), while others suggest delirium does not increase risk of patients dying (Levkoff et al., 1992; Wolters et al., 2014). The objective of this retrospective observational study was to determine if delirium is an independent predictor of mortality and develop a new model predicting three-month mortality of critically ill patients. Of the 165 patients followed in this study, 42 (25.5%) were deceased at three months and 123 (74.5%) survived. The most accurate model of predicting three-month mortality had an area under the curve of 0.89 (CI: 0.81 to 0.94), which included delirium burden defined as the fraction of the number of days patients were positive for individual features of delirium during their hospital stay. The main finding of the present study is the development of a new model that accurately predicts three-month mortality of critically ill patients. This study provides further evidence that delirium is an independent predictor of mortality and new evidence that delirium fraction improves the accuracy of a predictive models of mortality. We also identified individual features of delirium that are more predictive of mortality than others. Future research is needed to develop prevention measures and treatment interventions for delirium in the ICU and on hospital floors to reduce risk of patient mortality

A PK–PD model of ketamine-induced high-frequency oscillations

Objective. Ketamine is a widely used drug with clinical and research applications, and also known to be used as a recreational drug. Ketamine produces conspicuous changes in the electrocorticographic (ECoG) signals observed both in humans and rodents. In rodents, the intracranial ECoG displays a high-frequency oscillation (HFO) which power is modulated nonlinearly by ketamine dose. Despite the widespread use of ketamine there is no model description of the relationship between the pharmacokinetic–pharmacodynamics (PK–PDs) of ketamine and the observed HFO power. Approach. In the present study, we developed a PK–PD model based on estimated ketamine concentration, its known pharmacological actions, and observed ECoG effects. The main pharmacological action of ketamine is antagonism of the NMDA receptor (NMDAR), which in rodents is accompanied by an HFO observed in the ECoG. At high doses, however, ketamine also acts at non-NMDAR sites, produces loss of consciousness, and the transient disappearance of the HFO. We propose a two-compartment PK model that represents the concentration of ketamine, and a PD model based in opposing effects of the NMDAR and non-NMDAR actions on the HFO power. Main results. We recorded ECoG from the cortex of rats after two doses of ketamine, and extracted the HFO power from the ECoG spectrograms. We fit the PK–PD model to the time course of the HFO power, and showed that the model reproduces the dose-dependent profile of the HFO power. The model provides good fits even in the presence of high variability in HFO power across animals. As expected, the model does not provide good fits to the HFO power after dosing the pure NMDAR antagonist MK-801. Significance. Our study provides a simple model to relate the observed electrophysiological effects of ketamine to its actions at the molecular level at different concentrations. This will improve the study of ketamine and rodent models of schizophrenia to better understand the wide and divergent range of effects that ketamine has.National Institutes of Health (U.S.) (Pioneer Award DP1-OD003646)Burroughs Wellcome Fund (Career Award at the Scientific Interface)National Institutes of Health (U.S.) (Grant 5R01MH061976)National Institutes of Health (U.S.) (New Innovator Award DP2-OD006454

Thalamocortical synchronization during induction and emergence from propofol-induced unconsciousness

General anesthesia (GA) is a reversible drug-induced state of altered arousal required for more than 60,000 surgical procedures each day in the United States alone. Sedation and unconsciousness under GA are associated with stereotyped electrophysiological oscillations that are thought to reflect profound disruptions of activity in neuronal circuits that mediate awareness and cognition. Computational models make specific predictions about the role of the cortex and thalamus in these oscillations. In this paper, we provide in vivo evidence in rats that alpha oscillations (10–15 Hz) induced by the commonly used anesthetic drug propofol are synchronized between the thalamus and the medial prefrontal cortex. We also show that at deep levels of unconsciousness where movement ceases, coherent thalamocortical delta oscillations (1–5 Hz) develop, distinct from concurrent slow oscillations (0.1–1 Hz). The structure of these oscillations in both cortex and thalamus closely parallel those observed in the human electroencephalogram during propofol-induced unconsciousness. During emergence from GA, this synchronized activity dissipates in a sequence different from that observed during loss of consciousness. A possible explanation is that recovery from anesthesia-induced unconsciousness follows a “boot-up” sequence actively driven by ascending arousal centers. The involvement of medial prefrontal cortex suggests that when these oscillations (alpha, delta, slow) are observed in humans, self-awareness and internal consciousness would be impaired if not abolished. These studies advance our understanding of anesthesia-induced unconsciousness and altered arousal and further establish principled neurophysiological markers of these states.National Institutes of Health (U.S.) (Grant TR01GM104948)National Institutes of Health (U.S.) (Grant P01GM118269

Effects of Sevoflurane and Propofol on Frontal Electroencephalogram Power and Coherence

Background:: The neural mechanisms of anesthetic vapors have not been studied in depth. However, modeling and experimental studies on the intravenous anesthetic propofol indicate that potentiation of γ-aminobutyric acid receptors leads to a state of thalamocortical synchrony, observed as coherent frontal alpha oscillations, associated with unconsciousness. Sevoflurane, an ether derivative, also potentiates γ-aminobutyric acid receptors. However, in humans, sevoflurane-induced coherent frontal alpha oscillations have not been well detailed. Methods:: To study the electroencephalogram dynamics induced by sevoflurane, the authors identified age- and sex-matched patients in which sevoflurane (n = 30) or propofol (n = 30) was used as the sole agent for maintenance of general anesthesia during routine surgery. The authors compared the electroencephalogram signatures of sevoflurane with that of propofol using time-varying spectral and coherence methods. Results:: Sevoflurane general anesthesia is characterized by alpha oscillations with maximum power and coherence at approximately 10 Hz, (mean ± SD; peak power, 4.3 ± 3.5 dB; peak coherence, 0.73 ± 0.1). These alpha oscillations are similar to those observed during propofol general anesthesia, which also has maximum power and coherence at approximately 10 Hz (peak power, 2.1 ± 4.3 dB; peak coherence, 0.71 ± 0.1). However, sevoflurane also exhibited a distinct theta coherence signature (peak frequency, 4.9 ± 0.6 Hz; peak coherence, 0.58 ± 0.1). Slow oscillations were observed in both cases, with no significant difference in power or coherence. Conclusions:: The study results indicate that sevoflurane, like propofol, induces coherent frontal alpha oscillations and slow oscillations in humans to sustain the anesthesia-induced unconscious state. These results suggest a shared molecular and systems-level mechanism for the unconscious state induced by these drugs.National Institutes of Health (U.S.) (Grant DP2-OD006454)National Institutes of Health (U.S.) (Grant DP1-OD003646)National Institutes of Health (U.S.) (Grant TR01-GM104948

A Comparison of Propofol- and Dexmedetomidine-induced Electroencephalogram Dynamics Using Spectral and Coherence Analysis

Background:: Electroencephalogram patterns observed during sedation with dexmedetomidine appear similar to those observed during general anesthesia with propofol. This is evident with the occurrence of slow (0.1 to 1 Hz), delta (1 to 4 Hz), propofol-induced alpha (8 to 12 Hz), and dexmedetomidine-induced spindle (12 to 16 Hz) oscillations. However, these drugs have different molecular mechanisms and behavioral properties and are likely accompanied by distinguishing neural circuit dynamics. Methods:: The authors measured 64-channel electroencephalogram under dexmedetomidine (n = 9) and propofol (n = 8) in healthy volunteers, 18 to 36 yr of age. The authors administered dexmedetomidine with a 1-µg/kg loading bolus over 10 min, followed by a 0.7 µg kg−1 h−1 infusion. For propofol, the authors used a computer-controlled infusion to target the effect-site concentration gradually from 0 to 5 μg/ml. Volunteers listened to auditory stimuli and responded by button press to determine unconsciousness. The authors analyzed the electroencephalogram using multitaper spectral and coherence analysis. Results:: Dexmedetomidine was characterized by spindles with maximum power and coherence at approximately 13 Hz (mean ± SD; power, −10.8 ± 3.6 dB; coherence, 0.8 ± 0.08), whereas propofol was characterized with frontal alpha oscillations with peak frequency at approximately 11 Hz (power, 1.1 ± 4.5 dB; coherence, 0.9 ± 0.05). Notably, slow oscillation power during a general anesthetic state under propofol (power, 13.2 ± 2.4 dB) was much larger than during sedative states under both propofol (power, −2.5 ± 3.5 dB) and dexmedetomidine (power, −0.4 ± 3.1 dB). Conclusion:: The results indicate that dexmedetomidine and propofol place patients into different brain states and suggest that propofol enables a deeper state of unconsciousness by inducing large-amplitude slow oscillations that produce prolonged states of neuronal silence.National Institutes of Health (U.S.) (Grant DP2-OD006454)National Institutes of Health (U.S.) (Grant DP1-OD003646)National Institutes of Health (U.S.) (Grant TR01-GM104948