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1.
J Cardiothorac Vasc Anesth ; 37(9): 1700-1706, 2023 09.
Article in English | MEDLINE | ID: mdl-37217424

ABSTRACT

OBJECTIVES: This study aimed to evaluate whether a measure of subjective cognitive decline (SCD), the Patient-Reported Outcomes Measurement Information System (PROMIS) Applied Cognition-Abilities questionnaire, was associated with postoperative delirium. It was hypothesized that delirium during the surgical hospitalization would be associated with a decrease in subjective cognition up to 6 months after cardiac surgery. DESIGN: This was a secondary analysis of data from the Minimizing Intensive Care Unit Neurological Dysfunction with Dexmedetomidine-induced Sleep randomized, placebo-controlled, parallel-arm superiority trial. SETTING: Data from patients recruited between March 2017 and February 2022 at a tertiary medical center in Boston, Massachusetts were analyzed in February 2023. PARTICIPANTS: Data from 337 patients aged 60 years or older who underwent cardiac surgery with cardiopulmonary bypass were included. INTERVENTIONS: Patients were assessed preoperatively and postoperatively at 30, 90, and 180 days using the subjective PROMIS Applied Cognition-Abilities and telephonic Montreal Cognitive Assessment. MEASUREMENT AND MAIN RESULTS: Postoperative delirium occurred within 3 days in 39 participants (11.6%). After adjusting for baseline function, participants who developed postoperative delirium self-reported worse cognitive function (mean difference [MD] -2.64 [95% CI -5.25, -0.04]; p = 0.047) up to 180 days after surgery, as compared with nondelirious patients. This finding was consistent with those obtained from objective t-MoCA assessments (MD -0.77 [95% CI -1.49, -0.04]; p = 0.04). CONCLUSIONS: In this cohort of older patients undergoing cardiac surgery, in-hospital delirium was associated with SCD up to 180 days after surgery. This finding suggested that measures of SCD may enable population-level insights into the burden of cognitive decline associated with postoperative delirium.


Subject(s)
Cardiac Surgical Procedures , Cognitive Dysfunction , Delirium , Dexmedetomidine , Emergence Delirium , Humans , Aged , Dexmedetomidine/adverse effects , Delirium/chemically induced , Delirium/diagnosis , Delirium/epidemiology , Cardiac Surgical Procedures/adverse effects , Cognitive Dysfunction/chemically induced , Cognitive Dysfunction/diagnosis , Cognitive Dysfunction/epidemiology , Intensive Care Units , Sleep , Postoperative Complications/diagnosis , Postoperative Complications/epidemiology , Postoperative Complications/prevention & control
2.
Clin Neurophysiol ; 132(12): 3010-3018, 2021 12.
Article in English | MEDLINE | ID: mdl-34715426

ABSTRACT

OBJECTIVE: Ketamine is an anesthetic drug associated with dissociation. Decreased electroencephalogram alpha (8-13 Hz) and low-beta (13-20 Hz) oscillation power have been associated with ketamine-induced dissociation. We aimed to characterize surface electroencephalogram signatures that may serve as biomarkers for dissociation. METHODS: We analyzed data from a single-site, open-label, high-density surface electroencephalogram study of ketamine anesthesia (2 mg/kg, n = 15). We assessed dissociation longitudinally using the Clinician Administered Dissociation States Scale (CADSS) and administered midazolam to attenuate dissociation and enable causal inference. We analyzed electroencephalogram power and global coherence with multitaper spectral methods. Mixed effects models were used to assess whether power and global coherence signatures of ketamine could be developed into dissociation-specific biomarkers. RESULTS: Compared to baseline, ketamine unresponsiveness was associated with increased frontal power between 0.5 to 9.3 Hz, 12.2 to 16.6 Hz, and 24.4 to 50 Hz. As subjects transitioned into a responsive but dissociated state (mean CADSS ± SD, 22.1 ± 17), there was a decrease in power between 0.5 to 10.3 Hz and 11.7 to 50 Hz. Midazolam reduced dissociation scores (14.3 ± 11.6), decreased power between 4.4 to 11.7 Hz and increased power between 14.2 to 50 Hz. Our mixed-effects model demonstrated a quadratic relationship between time and CADSS scores. When models (frontal power, occipital power, global coherence) were reanalyzed with midazolam and electroencephalogram features as covariates, only midazolam was retained. CONCLUSIONS: Ketamine is associated with structured electroencephalogram power and global coherence signatures that may enable principled anesthetic state but not dissociation monitoring. SIGNIFICANCE: A neurophysiological biomarker for dissociation may lead to a better understanding of neuropsychiatric disorders.


Subject(s)
Anesthetics, Dissociative/pharmacology , Brain Waves/drug effects , Brain/drug effects , Ketamine/pharmacology , Adult , Brain/physiology , Brain Waves/physiology , Electroencephalography , Female , Humans , Male , Young Adult
3.
Pain Rep ; 6(2): e936, 2021.
Article in English | MEDLINE | ID: mdl-34104842

ABSTRACT

INTRODUCTION: Ketamine, an anesthetic adjunct, is routinely administered as part of a balanced general anesthetic technique. We recently showed that the acute analgesic and dissociation properties of ketamine are separable to suggest that distinct neural circuits underlie these states. OBJECTIVE: We aimed to study whether this finding is robust to the substantial neural circuit alterations associated with general anesthesia. METHODS: We conducted a single-site, open-label, randomized controlled, cross-over study of sevoflurane and sevoflurane-plus-ketamine (SK) general anesthesia in healthy subjects (n = 12). Before and after general anesthesia, we assessed precalibrated cuff pain intensity and nociceptive pain quality as well as dissociation using the Clinician-Administered Dissociative States Scale (CADSS). For statistical inference, we ran a variation of backward elimination repeated-measures analysis of covariance. Models with CADSS as a covariate term were used to assess whether dissociation mediated the effect of ketamine on pain intensity and quality. RESULTS: Sevoflurane-plus-ketamine general anesthesia was associated with a significant (P = 0.0002) pain intensity decline of 3 (SE, 0.44). There was an order effect for dissociation such that SK was associated with a significant (P = 0.0043) CADSS increase of 17.8 (3.2) when the SK treatment came first. When the pain intensity model was reanalyzed with CADSS as an additional covariate, the effect of CADSS was not significant. These results were also conserved for pain quality. CONCLUSIONS: Our findings suggest that the analgesic and dissociation properties of ketamine remain separable despite general anesthesia. Thus, ketamine may be used as a probe to advance our knowledge of dissociation independent pain circuits.

4.
J Sleep Res ; 30(5): e13322, 2021 10.
Article in English | MEDLINE | ID: mdl-33759264

ABSTRACT

Hospitalized older patients who undergo elective cardiac surgery with cardiopulmonary bypass are prone to postoperative delirium. Self-reported shorter sleep and longer sleep have been associated with impaired cognition. Few data exist to guide us on whether shorter or longer sleep is associated with postoperative delirium in this hospitalized cohort. This was a prospective, single-site, observational study of hospitalized patients (>60 years) scheduled to undergo elective major cardiac surgery with cardiopulmonary bypass (n = 16). We collected and analysed overnight polysomnography data using the Somté PSG device and assessed for delirium twice a day until postoperative day 3 using the long version of the confusion assessment method and a structured chart review. We also assessed subjective sleep quality using the Pittsburg Sleep Quality Index. The delirium median preoperative hospital stay of 9 [Q1, Q3: 7, 11] days was similar to the non-delirium preoperative hospital stay of 7 [4, 9] days (p = .154). The incidence of delirium was 45.5% (10/22) in the entire study cohort and 50% (8/16) in the final cohort with clean polysomnography data. The preoperative delirium median total sleep time of 323.8 [Q1, Q3: 280.3, 382.1] min was longer than the non-delirium median total sleep time of 254.3 [210.9, 278.1] min (p = .046). This was accounted for by a longer delirium median non-rapid eye movement (REM) stage 2 sleep duration of 282.3 [229.8, 328.8] min compared to the non-delirium median non-REM stage 2 sleep duration of 202.5 [174.4, 208.9] min (p = .012). Markov chain modelling confirmed these findings. There were no differences in measures of sleep quality assessed by the Pittsburg Sleep Quality Index. Polysomnography measures of sleep obtained the night preceding surgery in hospitalized older patients scheduled for elective major cardiac surgery with cardiopulmonary bypass are suggestive of an association between longer sleep duration and postoperative delirium.


Subject(s)
Cardiac Surgical Procedures , Delirium , Aged , Cardiac Surgical Procedures/adverse effects , Delirium/diagnosis , Delirium/epidemiology , Delirium/etiology , Humans , Polysomnography , Prospective Studies , Sleep
5.
J Racial Ethn Health Disparities ; 8(2): 384-393, 2021 04.
Article in English | MEDLINE | ID: mdl-32533531

ABSTRACT

Racial and ethnic disparities in pediatric anesthesia health services could result in minority children being at increased risk of poor outcomes, such as pain, anxiety, or over-exposure to medications. Yet, a comprehensive understanding of the literature on such disparities does not exist to date. The objective of this study is to describe health services disparities in pediatric anesthetic care in the pre-, intra-, or post-operative period by synthesizing current literature. We searched the National Library of Medicine's PubMed/Medline, Embase, and Web of Science for articles published between January 1, 2007, and May 9, 2020, to identify literature on racial and ethnic health services disparities in pediatric anesthesia. We used the Institute of Medicine's definition of disparities. Health services were related to pre-, intra-, or post-operative anesthetic care of pediatric patients (< 18 years old). Out of 2110 studies, 10 studies met the criteria for inclusion. Nine out of the ten articles were single-institutional observational studies, based at tertiary hospitals. Sample sizes ranged from 74 to 37,618 discrete participants, for a total of 69,350 subjects across all studies. Results of these studies present low-quality evidence and heterogeneous conclusions regarding pediatric anesthesia health services disparities. This review demonstrates the paucity and diversity of research on racial and ethnic disparities in pediatric anesthesia health services and suggests how future work might utilize improved data and rigorous study designs.


Subject(s)
Anesthesia , Healthcare Disparities/ethnology , Pediatrics , Child , Humans
6.
Anesthesiology ; 133(6): 1234-1243, 2020 12 01.
Article in English | MEDLINE | ID: mdl-33001139

ABSTRACT

BACKGROUND: The administration of dexmedetomidine is limited to highly monitored care settings because it is only available for use in humans as intravenous medication. An oral formulation of dexmedetomidine may broaden its use to all care settings. The authors investigated the effect of a capsule-based solid oral dosage formulation of dexmedetomidine on sleep polysomnography. METHODS: The authors performed a single-site, placebo-controlled, randomized, crossover, double-blind phase II study of a solid oral dosage formulation of dexmedetomidine (700 mcg; n = 15). The primary outcome was polysomnography sleep quality. Secondary outcomes included performance on the motor sequence task and psychomotor vigilance task administered to each subject at night and in the morning to assess motor memory consolidation and psychomotor function, respectively. Sleep questionnaires were also administered. RESULTS: Oral dexmedetomidine increased the duration of non-rapid eye movement (non-REM) stage 2 sleep by 63 (95% CI, 19 to 107) min (P = 0.010) and decreased the duration of rapid eye movement (REM) sleep by 42 (5 to 78) min (P = 0.031). Overnight motor sequence task performance improved after placebo sleep (7.9%; P = 0.003) but not after oral dexmedetomidine-induced sleep (-0.8%; P = 0.900). In exploratory analyses, we found a positive correlation between spindle density during non-REM stage 2 sleep and improvement in the overnight test performance (Spearman rho = 0.57; P = 0.028; n = 15) for placebo but not oral dexmedetomidine (Spearman rho = 0.04; P = 0.899; n = 15). Group differences in overnight motor sequence task performance, psychomotor vigilance task metrics, and sleep questionnaires did not meet the threshold for statistical significance. CONCLUSIONS: These results demonstrate that the nighttime administration of a solid oral dosage formulation of dexmedetomidine is associated with increased non-REM 2 sleep and decreased REM sleep. Spindle density during dexmedetomidine sleep was not associated with overnight improvement in the motor sequence task.


Subject(s)
Dexmedetomidine/pharmacology , Hypnotics and Sedatives/pharmacology , Sleep Stages/drug effects , Administration, Oral , Adult , Cross-Over Studies , Dexmedetomidine/administration & dosage , Double-Blind Method , Female , Humans , Hypnotics and Sedatives/administration & dosage , Male , Polysomnography
7.
Anesthesiology ; 133(5): 1021-1028, 2020 11 01.
Article in English | MEDLINE | ID: mdl-32898213

ABSTRACT

BACKGROUND: Ketamine is a dissociative anesthetic with analgesic properties. Ketamine's analgesic properties have been suggested to result from its dissociative properties. To the authors' knowledge, this postulate is unsubstantiated. The authors hypothesize that the dissociative and analgesic properties of ketamine are independent. METHODS: The authors conducted a single-site, open-label study of ketamine anesthesia (2 mg/kg) in 15 healthy subjects. Midazolam was administered at a prespecified time point to attenuate dissociation. The authors longitudinally assessed precalibrated cuff pain intensity and quality using Patient-Reported Outcomes Measurement Information System questionnaires, and dissociation, using the Clinician Administered Dissociative States Scale. Mixed effects models were used to assess whether dissociation accounted for the effect of ketamine on pain intensity and quality. RESULTS: The dissociation model demonstrated an inverted U-shaped quadratic relationship between time and dissociation scores. Additive to this effect, midazolam reduced the dissociation adjusted means by 10.3 points (95% CI, 3.4 to 17.1; P = 0.005). The pain intensity model also demonstrated a U-shaped quadratic relationship between time and pain intensity. When the pain intensity model was reanalyzed with dissociation scores as an additional covariate, the dissociation term was not retained in the model, and the other effects were preserved in direction and strength. This result was conserved for nociceptive and neuropathic pain quality. CONCLUSIONS: Ketamine's analgesic properties are not exclusively caused by dissociation. Thus, ketamine may be used as a probe to advance our knowledge of dissociation independent neural circuits that encode pain.


Subject(s)
Analgesics/administration & dosage , Anesthetics, Dissociative/administration & dosage , Electroencephalography/drug effects , Ketamine/administration & dosage , Pain Measurement/drug effects , Administration, Intravenous , Adult , Electroencephalography/methods , Female , Humans , Male , Pain Measurement/methods , Young Adult
8.
J Neural Eng ; 17(4): 046020, 2020 08 04.
Article in English | MEDLINE | ID: mdl-32485685

ABSTRACT

OBJECTIVE: The ability to monitor anesthetic states using automated approaches is expected to reduce inaccurate drug dosing and side-effects. Commercially available anesthetic state monitors perform poorly when ketamine is administered as an anesthetic-analgesic adjunct. Poor performance is likely because the models underlying these monitors are not optimized for the electroencephalogram (EEG) oscillations that are unique to the co-administration of ketamine. APPROACH: In this work, we designed two k-nearest neighbors algorithms for anesthetic state prediction. MAIN RESULTS: The first algorithm was trained only on sevoflurane EEG data, making it sevoflurane-specific. This algorithm enabled discrimination of the sevoflurane general anesthesia (GA) state from sedated and awake states (true positive rate = 0.87, [95% CI, 0.76, 0.97]). However, it did not enable discrimination of the sevoflurane-plus-ketamine GA state from sedated and awake states (true positive rate = 0.43, [0.19, 0.67]). In our second algorithm, we implemented a cross drug training paradigm by including both sevoflurane and sevoflurane-plus-ketamine EEG data in our training set. This algorithm enabled discrimination of the sevoflurane-plus-ketamine GA state from sedated and awake states (true positive rate = 0.91, [0.84, 0.98]). SIGNIFICANCE: Instead of a one-algorithm-fits-all-drugs approach to anesthetic state monitoring, our results suggest that drug-specific models are necessary to improve the performance of automated anesthetic state monitors.


Subject(s)
Anesthetics, Inhalation , Pharmaceutical Preparations , Electroencephalography , Machine Learning , Sevoflurane
9.
Anesthesiology ; 133(2): 280-292, 2020 08.
Article in English | MEDLINE | ID: mdl-32349072

ABSTRACT

BACKGROUND: Intraoperative burst-suppression is associated with postoperative delirium. Whether this association is causal remains unclear. Therefore, the authors investigated whether burst-suppression during cardiopulmonary bypass (CPB) mediates the effects of known delirium risk factors on postoperative delirium. METHODS: This was a retrospective cohort observational substudy of the Minimizing ICU [intensive care unit] Neurological Dysfunction with Dexmedetomidine-induced Sleep (MINDDS) trial. The authors analyzed data from patients more than 60 yr old undergoing cardiac surgery (n = 159). Univariate and multivariable regression analyses were performed to assess for associations and enable causal inference. Delirium risk factors were evaluated using the abbreviated Montreal Cognitive Assessment and Patient-Reported Outcomes Measurement Information System questionnaires for applied cognition, physical function, global health, sleep, and pain. The authors also analyzed electroencephalogram data (n = 141). RESULTS: The incidence of delirium in patients with CPB burst-suppression was 25% (15 of 60) compared with 6% (5 of 81) in patients without CPB burst-suppression. In univariate analyses, age (odds ratio, 1.08 [95% CI, 1.03 to 1.14]; P = 0.002), lowest CPB temperature (odds ratio, 0.79 [0.66 to 0.94]; P = 0.010), alpha power (odds ratio, 0.65 [0.54 to 0.80]; P < 0.001), and physical function (odds ratio, 0.95 [0.91 to 0.98]; P = 0.007) were associated with CPB burst-suppression. In separate univariate analyses, age (odds ratio, 1.09 [1.02 to 1.16]; P = 0.009), abbreviated Montreal Cognitive Assessment (odds ratio, 0.80 [0.66 to 0.97]; P = 0.024), alpha power (odds ratio, 0.75 [0.59 to 0.96]; P = 0.025), and CPB burst-suppression (odds ratio, 3.79 [1.5 to 9.6]; P = 0.005) were associated with delirium. However, only physical function (odds ratio, 0.96 [0.91 to 0.99]; P = 0.044), lowest CPB temperature (odds ratio, 0.73 [0.58 to 0.88]; P = 0.003), and electroencephalogram alpha power (odds ratio, 0.61 [0.47 to 0.76]; P < 0.001) were retained as predictors in the burst-suppression multivariable model. Burst-suppression (odds ratio, 4.1 [1.5 to 13.7]; P = 0.012) and age (odds ratio, 1.07 [0.99 to 1.15]; P = 0.090) were retained as predictors in the delirium multivariable model. Delirium was associated with decreased electroencephalogram power from 6.8 to 24.4 Hertz. CONCLUSIONS: The inference from the present study is that CPB burst-suppression mediates the effects of physical function, lowest CPB temperature, and electroencephalogram alpha power on delirium.


Subject(s)
Cardiac Surgical Procedures , Delirium , Aged , Cardiopulmonary Bypass , Electroencephalography , Humans , Retrospective Studies
10.
Commun Biol ; 2: 415, 2019.
Article in English | MEDLINE | ID: mdl-31754645

ABSTRACT

Understanding anesthetic mechanisms with the goal of producing anesthetic states with limited systemic side effects is a major objective of neuroscience research in anesthesiology. Coherent frontal alpha oscillations have been postulated as a mechanism of sevoflurane general anesthesia. This postulate remains unproven. Therefore, we performed a single-site, randomized, cross-over, high-density electroencephalogram study of sevoflurane and sevoflurane-plus-ketamine general anesthesia in 12 healthy subjects. Data were analyzed with multitaper spectral, global coherence, cross-frequency coupling, and phase-dependent methods. Our results suggest that coherent alpha oscillations are not fundamental for maintaining sevoflurane general anesthesia. Taken together, our results suggest that subanesthetic and general anesthetic sevoflurane brain states emerge from impaired information processing instantiated by a delta-higher frequency phase-amplitude coupling syntax. These results provide fundamental new insights into the neural circuit mechanisms of sevoflurane anesthesia and suggest that anesthetic states may be produced by extracranial perturbations that cause delta-higher frequency phase-amplitude interactions.


Subject(s)
Anesthesia, General , Anesthetics, Inhalation/pharmacology , Neurons/drug effects , Neurons/metabolism , Sevoflurane/pharmacology , Synaptic Transmission/drug effects , Anesthetics, Inhalation/administration & dosage , Electroencephalography , Electrophysiological Phenomena , Humans , Sevoflurane/administration & dosage
11.
Annu Int Conf IEEE Eng Med Biol Soc ; 2019: 5808-5811, 2019 Jul.
Article in English | MEDLINE | ID: mdl-31947172

ABSTRACT

Maintaining anesthetic states using automated brain-state prediction systems is expected to reduce drug overdosage and associated side-effects. However, commercially available brain-state monitoring systems perform poorly on drug-class combinations. We assume that current automated brain-state prediction systems perform poorly because they do not account for brain-state dynamics that are unique to drug-class combinations. In this work, we develop a k-nearest neighbors model to test whether improvements to automated brain-state prediction of drug-class combinations are feasible. We utilize electroencephalogram data collected from human subjects who received general anesthesia with sevoflurane and general anesthesia with the drug-class combination of sevoflurane-plus-ketamine. We demonstrate improved performance predicting anesthesia-induced brain-states using drug-specific models.


Subject(s)
Anesthetics, Inhalation , Brain , Anesthesia, General , Electroencephalography , Humans , Methyl Ethers
12.
J Neurophysiol ; 117(3): 1057-1069, 2017 03 01.
Article in English | MEDLINE | ID: mdl-28003412

ABSTRACT

Neuronal cell identity is established during development and must be maintained throughout an animal's life (Fishell G, Heintz N. Neuron 80: 602-612, 2013). Transcription factors critical for establishing neuronal identity can be required for maintaining it (Deneris ES, Hobert O. Nat Neurosci 17: 899-907, 2014). Posttranscriptional regulation also plays an important role in neuronal differentiation (Bian S, Sun T. Mol Neurobiol 44: 359-373, 2011), but its role in maintaining cell identity is less established. To better understand how posttranscriptional regulation might contribute to cell identity, we examined the proprioceptive neurons in the dorsal root ganglion (DRG), a highly specialized sensory neuron class, with well-established properties that distinguish them from other neurons in the ganglion. By conditionally ablating Dicer in mice, using parvalbumin (Pvalb)-driven Cre recombinase, we impaired posttranscriptional regulation in the proprioceptive sensory neuron population. Knockout (KO) animals display a progressive form of ataxia at the beginning of the fourth postnatal week that is accompanied by a cell death within the DRG. Before cell loss, expression profiling shows a reduction of proprioceptor specific genes and an increased expression of nonproprioceptive genes normally enriched in other ganglion neurons. Furthermore, although central connections of these neurons are intact, the peripheral connections to the muscle are functionally impaired. Posttranscriptional regulation is therefore necessary to retain the transcriptional identity and support functional specialization of the proprioceptive sensory neurons.NEW & NOTEWORTHY We have demonstrated that selectively impairing Dicer in parvalbumin-positive neurons, which include the proprioceptors, triggers behavioral changes, a lack of muscle connectivity, and a loss of transcriptional identity as observed through RNA sequencing. These results suggest that Dicer and, most likely by extension, microRNAs are crucially important for maintaining proprioception. Additionally, this study hints at the larger question of how neurons maintain their functional and molecular specificity.


Subject(s)
Ataxia/physiopathology , DEAD-box RNA Helicases/physiology , Ganglia, Spinal/physiology , Proprioception , Protein Processing, Post-Translational , Ribonuclease III/physiology , Sensory Receptor Cells/physiology , Animals , Ataxia/genetics , Cell Death , DEAD-box RNA Helicases/genetics , DEAD-box RNA Helicases/metabolism , Ganglia, Spinal/metabolism , Mice , Mice, Knockout , Muscle Spindles/physiology , Muscle, Skeletal/cytology , Parvalbumins/metabolism , Ribonuclease III/genetics , Ribonuclease III/metabolism , Sensory Receptor Cells/metabolism , Vesicular Glutamate Transport Protein 1/metabolism
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