Analysis of the Hindriks and van Putten model for propofol anesthesia: Limitations and extensions.

We present a detailed analysis of the Hindriks and van Putten thalamocortical mean-field model for propofol anesthesia [NeuroImage 60(23), 2012]. The Hindriks and van Putten (HvP) model predicts increases in delta and alpha power for moderate (up to 130%) prolongation of GABAA inhibitory response, corresponding to light anesthetic sedation. Our analysis reveals that, for deeper anesthetic effect, the model exhibits an unexpected abrupt jump in cortical activity from a low-firing state to an extremely high-firing stable state (∼250 spikes/s), and remains locked there even at GABAA prolongations as high as 300% which would be expected to induce full comatose suppression of all firing activity. We demonstrate that this unphysiological behavior can be completely suppressed with appropriate tuning of the parameters controlling the sigmoidal functions that map soma voltage to firing rate for the excitatory and inhibitory neural populations, coupled with elimination of the putative population-dependent anesthetic efficacies introduced in the HvP model. The modifications reported here constrain the anesthetized brain activity into a biologically plausible range in which the cortex now has access to a moderate-firing state ("awake") and a low-firing ("anesthetized") state such that the brain can transition from "awake" to "anesthetized" states at a critical level of drug concentration. The modified HvP model predicts a drug-effect hysteresis in which the drug concentration required for induction is larger than that at emergence. In addition, the revised model shows a decrease in the intensity and frequency of alpha-band fluctuations, transitioning to delta-band dominance, with deepening anesthesia. These predicted drug concentration-dependent changes in EEG dynamics are consistent with clinical reports.

[The quantitative EEG in electroencephalogram-based brain monitoring during general anesthesia]. / Das quantifizierte EEG im elektroenzephalogrammbasierten Monitoring während Allgemeinanästhesie.

The electroencephalogram (EEG) is increasingly being used in the clinical routine of anesthesia in German-speaking countries. In over 90% of patients the frontal EEG changes somewhat predictably in response to administration of the normally used anesthetic agents (propofol and volatile gasses). An adequate depth of anesthesia and appropriate concentrations of anesthetics in the brain generate mostly frontal oscillations between 8 and 12 Hz as well as slow delta waves between 0.5 and 4 Hz. The frontal EEG channel is well-suited for avoidance of insufficient depth of anesthesia and excessive administration of anesthetics. This article explains the clinical interpretation of the most important EEG patterns and the biophysical background. Also discussed are important limitations and pitfalls for the clinical routine, which the anesthetist should know in order to utilize the EEG as an admittedly incomplete but clinically extremely important parameter for the level of consciousness.

Association of electroencephalogram trajectories during emergence from anaesthesia with delirium in the postanaesthesia care unit: an early sign of postoperative complications.

BACKGROUND: Postoperative delirium is associated with an increased risk of morbidity and mortality, especially in the elderly. Delirium in the postanaesthesia care unit (PACU) could predict adverse clinical outcomes. METHODS: We investigated a potential link between intraoperative EEG patterns and PACU delirium as well as an association of PACU delirium with perioperative outcomes, readmission and length of hospital stay. The risk factors for PACU delirium were also explored. Data were collected from 626 patients receiving general anaesthesia for procedures that would not interfere with frontal EEG recording. RESULTS: Of the 626 subjects enrolled, 125 tested positive for PACU delirium. Whilst age, renal failure, and pre-existing neurological disease were associated with PACU delirium in the univariable analysis, the multivariable analysis revealed the importance of information derived from the EEG, anaesthetic technique, anaesthesia duration, and history of stroke or neurodegenerative disease. The occurrence of EEG burst suppression during maintenance [odds ratio (OR)=1.86 (1.13-3.05)] and the type of EEG emergence trajectory may be predictive of PACU delirium. Specifically, EEG emergence trajectories lacking significant spindle power were strongly associated with PACU delirium, especially in cases that involved ketamine or nitrous oxide [OR=6.51 (3.00-14.12)]. Additionally, subjects with PACU delirium were at an increased risk for readmission [OR=2.17 (1.13-4.17)] and twice as likely to stay >6 days in the hospital. CONCLUSIONS: Specific EEG patterns were associated with PACU delirium. These findings provide valuable information regarding how the brain reacts to surgery and anaesthesia that may lead to strategies to predict PACU delirium and identify key areas of investigation for its prevention.

General anaesthesia as fragmentation of selfhood: insights from electroencephalography and neuroimaging.

Selfhood is linked to brain processes that enable the experience of a person as a distinct entity, capable of agency. This framework naturally incorporates a continuum of both non-conscious and conscious self-related information processing, and includes a hierarchy of components, such as awareness of existence (core self), embodied self (sentience), executive self (agency/volition), and various other higher-order cognitive processes. Consciousness relates to, but is not congruent, with selfhood; understanding the processes required for selfhood can explain the partial consciousness seen in anaesthesia. Functional-brain-imaging and electroencephalographic studies in sleep and general anaesthesia have shown differential effects of anaesthetic drugs on various specific self-related functional brain networks. In particular, drug-induced selective impairment of anterior insula function suggests there might be a crucial difference between anaesthesia and natural sleep when it comes to the salience network. With increasing concentrations of anaesthetics, it is not uncommon for patients to become depersonalised (i.e. to lose sentience and agency), but retain many higher-order functions and a disembodied self-awareness, until quite high concentrations are reached. In this respect, general anaesthesia differs significantly from physiological sleep, where it appears that loss of agency and sentience parallels, or lags behind, the decrease in self-awareness. Interestingly, connectivity within the posterior brain regions is maintained even to quite high concentrations of anaesthetics, potentially representing a pathognomonic marker of the core self that possibly is involved in maintaining a reduced energy state of homeostasis.

Propofol-induced unresponsiveness is associated with impaired feedforward connectivity in cortical hierarchy.

BACKGROUND: Impaired consciousness has been associated with impaired cortical signal propagation after transcranial magnetic stimulation (TMS). We hypothesised that the reduced current propagation under propofol-induced unresponsiveness is associated with changes in both feedforward and feedback connectivity across the cortical hierarchy. METHODS: Eight subjects underwent left occipital TMS coupled with high-density EEG recordings during wakefulness and propofol-induced unconsciousness. Spectral analysis was applied to responses recorded from sensors overlying six hierarchical cortical sources involved in visual processing. Dynamic causal modelling (DCM) of induced time-frequency responses and evoked response potentials were used to investigate propofol's effects on connectivity between regions. RESULTS: Sensor space analysis demonstrated that propofol reduced both induced and evoked power after TMS in occipital, parietal, and frontal electrodes. Bayesian model selection supported a DCM with hierarchical feedforward and feedback connections. DCM of induced EEG responses revealed that the primary effect of propofol was impaired feedforward responses in cross-frequency theta/alpha-gamma coupling and within frequency theta coupling (F contrast, family-wise error corrected P<0.05). An exploratory analysis (thresholded at uncorrected P<0.001) also suggested that propofol impaired feedforward and feedback beta band coupling. Post hoc analyses showed impairments in all feedforward connections and one feedback connection from parietal to occipital cortex. DCM of the evoked response potential showed impaired feedforward connectivity between left-sided occipital and parietal cortex (T contrast P=0.004, Bonferroni corrected). CONCLUSIONS: Propofol-induced loss of consciousness is associated with impaired hierarchical feedforward connectivity assessed by EEG after occipital TMS.

Frontal alpha-delta EEG does not preclude volitional response during anaesthesia: prospective cohort study of the isolated forearm technique.

BACKGROUND: The isolated forearm test (IFT) is the gold standard test of connected consciousness (awareness of the environment) during anaesthesia. The frontal alpha-delta EEG pattern (seen in slow wave sleep) is widely held to indicate anaesthetic-induced unconsciousness. A priori we proposed that one responder with the frontal alpha-delta EEG pattern would falsify this concept. METHODS: Frontal EEG was recorded in a subset of patients from three centres participating in an international multicentre study of IFT responsiveness following tracheal intubation. Raw EEG waveforms were analysed for power-frequency spectra, depth-of-anaesthesia indices, permutation entropy, slow wave activity saturation and alpha-delta amplitude-phase coupling. RESULTS: Volitional responses to verbal command occurred in six out of 90 patients. Three responses occurred immediately following intubation in patients (from Sites 1 and 2) exhibiting an alpha-delta dominant (delta power >20 dB, alpha power >10 dB) EEG pattern. The power-frequency spectra obtained during these responses were similar to those of non-responders (P>0.05) at those sites. A further three responses occurred in (Site 3) patients not exhibiting the classic alpha-delta EEG pattern; these responses occurred later relative to intubation, and in patients had been co-administered ketamine and less volatile anaesthetic compared with Site 1 and 2 patients. None of the derived depth-of-anaesthesia indices could robustly discrimate IFT responders and non-responders. CONCLUSIONS: Connected consciousness can occur in the presence of the frontal alpha-delta EEG pattern during anaesthesia. Frontal EEG parameters do not readily discriminate volitional responsiveness (a marker of connected consciousness) and unresponsiveness during anaesthesia. CLINICAL TRIAL REGISTRATION: NCT02248623.

Brain functional connectivity differentiates dexmedetomidine from propofol and natural sleep.

BACKGROUND: We used functional connectivity measures from brain resting state functional magnetic resonance imaging to identify human neural correlates of sedation with dexmedetomidine or propofol and their similarities with natural sleep. METHODS: Connectivity within the resting state networks that are proposed to sustain consciousness generation was compared between deep non-rapid-eye-movement (N3) sleep, dexmedetomidine sedation, and propofol sedation in volunteers who became unresponsive to verbal command. A newly acquired dexmedetomidine dataset was compared with our previously published propofol and N3 sleep datasets. RESULTS: In all three unresponsive states (dexmedetomidine sedation, propofol sedation, and N3 sleep), within-network functional connectivity, including thalamic functional connectivity in the higher-order (default mode, executive control, and salience) networks, was significantly reduced as compared with the wake state. Thalamic functional connectivity was not reduced for unresponsive states within lower-order (auditory, sensorimotor, and visual) networks. Voxel-wise statistical comparisons between the different unresponsive states revealed that thalamic functional connectivity with the medial prefrontal/anterior cingulate cortex and with the mesopontine area was reduced least during dexmedetomidine-induced unresponsiveness and most during propofol-induced unresponsiveness. The reduction seen during N3 sleep was intermediate between those of dexmedetomidine and propofol. CONCLUSIONS: Thalamic connectivity with key nodes of arousal and saliency detection networks was relatively preserved during N3 sleep and dexmedetomidine-induced unresponsiveness as compared to propofol. These network effects may explain the rapid recovery of oriented responsiveness to external stimulation seen under dexmedetomidine sedation. TRIAL REGISTRY NUMBER: Committee number: 'Comité d'Ethique Hospitalo-Facultaire Universitaire de Liège' (707); EudraCT number: 2012-003562-40; internal reference: 20121/135; accepted on August 31, 2012; Chair: Prof G. Rorive. As it was considered a phase I clinical trial, this protocol does not appear on the EudraCT public website.

Self-administered methoxyflurane for procedural analgesia: experience in a tertiary Australasian centre.

Methoxyflurane, an agent formerly used as a volatile anaesthetic but that has strong analgesic properties, will soon become available again in the UK and Europe in the form of a small hand-held inhaler. We describe our experience in the use of inhaled methoxyflurane for procedural analgesia within a large tertiary hospital. In a small pilot crossover study of patients undergoing burns-dressing procedures, self-administered methoxyflurane inhalation was preferred to ketamine-midazolam patient-controlled analgesia by five of eight patients. Patient and proceduralist outcomes and satisfaction were recorded from a subsequent case series of 173 minor surgical and radiological procedures in 123 patients performed using inhaled methoxyflurane. The procedures included change of dressing, minor debridement, colonoscopy and incision-and-drainage of abscess. There was a 97% success rate of methoxyflurane analgesia to facilitate these procedures. Limitations of methoxyflurane include maximal daily and weekly doses, and uncertainty regarding its safety in patients with pre-existing renal disease.

Randomized controlled trial of the effect of depth of anaesthesia on postoperative pain.

BACKGROUND: Our hypothesis was that deep anaesthesia, as estimated by a low target bispectral index (BIS) of 30-40, would result in less postoperative pain than that achieved at a conventional depth of anaesthesia. METHODS: We undertook a randomized double-blind controlled study at two tertiary teaching hospitals in New Zealand (2010-1) recruiting 135 adult patients ASA I-II presenting for non-emergent surgery under general anaesthesia requiring tracheal intubation. Anaesthesia was maintained with desflurane and a multimodal analgesia regimen comprising fentanyl infusion, i.v. paracetamol, and parecoxib. Patients were randomly assigned to either a low BIS (30-40) group or a high BIS (45-60) group. Desflurane concentrations were titrated to achieve these targets. Postoperative pain was assessed by: the pain on awakening (0-10, verbal rating scale, VRS(awake)) in the post-anaesthetic care unit; pain on activity at 20-24 h after operation (VRS(d1A)); and the rate of morphine patient-controlled analgesia (PCA) usage over the first 24 h. RESULTS: There was no statistically significant difference between the two groups for any of the pain scores. The median [inter-quartile range (IQR)] VRS(awake) was 4.0 (0-8) for the low and 4.0 (0-8) for the high BIS groups (P=0.56). The median (IQR) VRS(d1A) was 3.0 (1-5) for the low and 3.0 (1.5-4.5) for the high BIS groups (P=0.83). The median PCA morphine consumption in the low BIS group was 0.61 mg h(-1) (0.04-1.5) vs 0.43 mg h(-1) (0-1.59) in the high BIS group (P=0.98). CONCLUSIONS: We conclude that there is no clinically useful analgesic effect of a deep anaesthesia regimen.

Pharmacokinetics of dexmedetomidine combined with therapeutic hypothermia in a piglet asphyxia model.

BACKGROUND: The highly selective α2 -adrenoreceptor agonist, dexmedetomidine, exerts neuroprotective, analgesic, anti-inflammatory and sympatholytic properties that may be beneficial for perinatal asphyxia. The optimal safe dose for pre-clinical newborn neuroprotection studies is unknown. METHODS: Following cerebral hypoxia-ischaemia, dexmedetomidine was administered to nine newborn piglets in a de-escalation dose study in combination with hypothermia (whole body cooling to 33.5°C). Dexmedetomidine was administered with a loading dose of 1 µg/kg and maintenance infusion at doses from 10 to 0.6 µg/kg/h. One additional piglet was not subjected to hypoxia-ischaemia. Blood for pharmacokinetic analysis was sampled pre-insult and frequently post-insult. A one-compartment linear disposition model was used to fit data. Population parameter estimates were obtained using non-linear mixed effects modelling. RESULTS: All dexmedetomidine infusion regimens led to plasma concentrations above those associated with sedation in neonates and children (0.4-0.8 µg/l). Seven out of the nine piglets with hypoxia-ischaemia experienced periods of bradycardia, hypotension, hypertension and cardiac arrest; all haemodynamic adverse events occurred in piglets with plasma concentrations greater than 1 µg/l. Dexmedetomidine clearance was 0.126 l/kg/h [coefficient of variation (CV) 46.6.%] and volume of distribution was 3.37 l/kg (CV 191%). Dexmedetomidine clearance was reduced by 32.7% at a temperature of 33.5°C. Dexmedetomidine clearance was reduced by 55.8% following hypoxia-ischaemia. CONCLUSIONS: Dexmedetomidine clearance was reduced almost tenfold compared with adult values in the newborn piglet following hypoxic-ischaemic brain injury and subsequent therapeutic hypothermia. Reduced clearance was related to cumulative effects of both hypothermia and exposure to hypoxia. High plasma levels of dexmedetomidine were associated with major cardiovascular complications.

Cross-frequency coupling during isoflurane anaesthesia as revealed by electroencephalographic harmonic wavelet bicoherence.

BACKGROUND: Fourier bicoherence has previously been applied to investigate phase coupling in the EEG in anaesthesia. However, there are significant theoretical limitations regarding its sensitivity in detecting transient episodes of inter-frequency coupling. Therefore, we used a recently developed wavelet bicoherence method to investigate the cross-frequency coupling in the EEG of patients under isoflurane anaesthesia; examining the relationship between the patterns of wavelet bicoherence and the isoflurane concentrations. METHODS: We analysed a set of previously published EEG data, obtained from 29 patients who underwent elective abdominal surgery under isoflurane anaesthesia. Artifact-free, 1 min EEG segments at different isoflurane concentrations were extracted from each subject and the wavelet bicoherence calculated for all pairs of frequencies from 0.5 to 20 Hz. RESULTS: Isoflurane caused two peaks in the α (6-13 Hz) and slow δ (<1 Hz) regions of the bicoherence matrix diagonal. Higher concentrations of isoflurane shifted the α peak to lower frequencies [11.3 (0.9) Hz at 0.3% to 7.1 (1.2) Hz at 1.5%], as has been previously observed in the power spectra. Outside the diagonal, we also found a significant α peak that was phase-coupled to the slow δ waves; higher concentrations of isoflurane shifted this peak to lower frequencies [10.8 (1.2) to 7.7 (0.7) Hz]. CONCLUSIONS: Isoflurane caused cross-frequency coupling between α and slow δ waves. Increasing isoflurane concentration slowed the α frequencies where the coupling had occurred. This phenomenon of α-δ coupling suggests that slow cortical oscillations organize the higher α band activity, which is consistent with other studies in natural sleep.