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.

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.

Spinodal decomposition in a mean-field model of the cortex: Emergence of hexagonally symmetric activation patterns.

Spinodal decomposition is a well-known pattern-forming mechanism in metallurgic alloys, semiconductor crystals, and colloidal gels. In metallurgy, if a heated sample of a homogeneous Zn-Al alloy is suddenly quenched below a critical temperature, then the sample can spontaneously precipitate into inhomogenous textures of Zn- and Al-rich regions with significantly altered material properties such as ductility and hardness. Here we report on our recent discovery that a two-dimensional model of the human cortex with inhibitory diffusion can, under particular homogeneous initial conditions, exhibit a form of nonconserved spinodal decomposition in which regions of the cortex self-organize into hexagonally distributed binary patches of activity and inactivity. Fine-scale patterns precipitate rapidly, and then the dynamics slows to render coarser-scale shapes which can ripen into a range of slowly evolving patterns including mazelike labyrinths, hexagonal islands and continents, nucleating "mitotic cells" which grow to a critical size then subdivide, and inverse nucleations in which quiescent islands are surrounded by a sea of activity. One interesting class of activity coalesces into a soliton-like narrow ribbon of depolarization that traverses the cortex at ∼4cm/s. We speculate that this may correspond to the thus far unexplained interictal waves of cortical activation that precede grand-mal seizure in an epileptic event. We note that spinodal decomposition is quite distinct from the Turing mechanism for symmetry breaking in cortex investigated in earlier work by the authors [Steyn-Ross et al., Phys. Rev. E 76, 011916 (2007)PLEEE81539-375510.1103/PhysRevE.76.011916].

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.

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.

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.

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.

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.

Using the Hilbert-Huang transform to measure the electroencephalographic effect of propofol.

Monitoring the effect of anesthetic drugs on the central nervous system is a major ongoing challenge in anesthesia research. A number of electroencephalogram (EEG)-based monitors of the anesthetic drug effect such as the bispectral (BIS) index have been proposed to analyze the EEG signal during anesthesia. However, the BIS index has received some criticism. This paper offers a method based on the Hilbert-Huang transformation to calculate an index, called the Hilbert-Huang weighted regional frequency (HHWRF), to quantify the effect of propofol on brain activity. The HHWRF and BIS indices are applied to EEG signals collected from nine patients during a controlled propofol induction and emergence scheme. The results show that both the HHWRF and BIS track the gross changes in the EEG with increasing and decreasing anesthetic drug effect (the prediction probability P(k) of 0.85 and 0.83 for HHWRF and BIS, respectively). Our new index can reflect the transition from unconsciousness to consciousness faster than the BIS, as indicated from the pharmacokinetic and pharmacodynamic modeled parameters and also from the analysis around the point of reawakening. This method could be used to design a new EEG monitoring system to estimate the propofol anesthetic drug effect.

The role of connexin36 gap junctions in modulating the hypnotic effects of isoflurane and propofol in mice.

Gap junction blockade is a possible mechanism by which general anaesthetic drugs cause unconsciousness. We measured the sensitivity of connexin36 knockout mice to the hypnotic effects of isoflurane and propofol. The experimental endpoint was recovery of the righting reflex of the anaesthetised animals during 0.2% step-reductions in isoflurane concentration, or following intraperitoneal injection of propofol (100 mg.kg(-1) ). Connexin36 knockout animals were more sensitive to the hypnotic effects of isoflurane than 'normal' wild-type animals. The half maximal effective concentration (EC50) for recovery of righting reflex was 0.37% for connexin36 knockout vs 0.49% for wild-type animals (p < 0.001). For propofol, connnexin36 knockout animals showed more rapid loss of righting reflex than wild-type animals (mean (SD) 2.8 (0.13) vs 3.8 (0.27) min); and young (< 60 days) connexin36 knockout animals remained anaesthetised for longer than young wild-type mice (47.2 (2.9) vs 30.5 (1.7) min; p < 0.00001). These findings suggest that the hypnotic effects of anaesthetic drugs may be moderately enhanced by gap junction blockade.

A mechanism for ultra-slow oscillations in the cortical default network.

When the brain is in its noncognitive "idling" state, functional MRI measurements reveal the activation of default cortical networks whose activity is suppressed during cognitive processing. This default or background mode is characterized by ultra-slow BOLD oscillations (∼0.05 Hz), signaling extremely slow cycling in cortical metabolic demand across distinct cortical regions. Here we describe a model of the cortex which predicts that slow cycling of cortical activity can arise naturally as a result of nonlinear interactions between temporal (Hopf) and spatial (Turing) instabilities. The Hopf instability is triggered by delays in the inhibitory postsynaptic response, while the Turing instability is precipitated by increases in the strength of the gap-junction coupling between interneurons. We comment on possible implications for slow dendritic computation and information processing.

Changes in airway configuration with different head and neck positions using magnetic resonance imaging of normal airways: a new concept with possible clinical applications.

BACKGROUND: The sniffing position is often considered optimal for direct laryngoscopy. Another concept of airway configuration involving a laryngeal vestibule axis and two curves has also been suggested. We investigated whether this theory can be supported mathematically and if it supports the sniffing position as being optimal for direct laryngoscopy. METHODS: Magnetic resonance imaging scans were performed in 42 normal adult volunteers. The airway passage was divided into two curves-primary (oro-pharyngeal curve) and secondary (pharyngo-glotto-tracheal curve). Airway configuration was evaluated in the neutral, extension, head lift, and sniffing positions. The airway passage, point of inflection (where the two curves meet), its tangent, and the line of sight were plotted on each scan. RESULTS: The point of inflection lay within the laryngeal vestibule in all positions. The head lift and sniffing positions caused the tangent to the point of inflection to approximate the horizontal plane. The sniffing, extension, and head lift positions caused a reduction in the area between the line of sight and the airway curve compared with the neutral position. CONCLUSIONS: A two-curve theory is proposed as a basis for explaining airway configuration. The changes in these curves with head and neck positioning support the sniffing position as optimal for direct laryngoscopy. Application of this new concept to other forms of laryngoscopy should be investigated.

Episodic waveforms in the electroencephalogram during general anaesthesia: a study of patterns of response to noxious stimuli.

Previous studies of the electroencephalogram (EEG) during anaesthesia have identified two distinct patterns of change in response to a noxious stimulus, a classical arousal pattern and a paradoxical arousal pattern. We developed methods of EEG analysis to quantify episodic EEG patterns--namely sleep spindle-like ('10 Hz-score') and burst-suppression-like fluctuations in high frequencies ('high frequency variation index')--and used traditional power spectral quantification of non-episodic delta waves. We studied 30 healthy adult patients undergoing elective surgery under general anaesthesia with propofol, fentanyl (1.0, 2.5 or 4.0 microg/kg, n=10 for each group), muscle relaxant and sevoflurane. Prefrontal EEG data were recorded during the operation and analysed for changes in episodic patterns before and after noxious stimuli (intubation and incision). Before noxious stimuli, the EEG patterns varied markedly between patients and were not strongly correlated to calculated effect-site concentrations of fentanyl, propofol or sevoflurane. Noxious stimuli reduced the 10 Hz-score from 0.25 to 0.20 (P = 0.01) after intubation and from 0.33 to 0.27 (P = 0.01) after incision; and high frequency variation index from 2.8 to 2.0 (P=0.02) after incision--the classical arousal pattern. The nociception-induced reduction in spindles was greater in the low-dose fentanyl group (P = 0.01). There was less tachycardia in the high-dose fentanyl group (P = 0.002). It is possible to quantify such episodic EEG patterns during general anaesthesia and in this study noxious stimulation tended to reduce the prevalence of these patterns.

A failure of M-Entropy to correctly detect burst suppression leading to sevoflurane overdosage.

Electroencephalogram depth of anaesthesia monitors are increasingly being used, with the aim of reducing awareness during anaesthesia. Most literature concentrates on the ability of these monitors to predict when a patient is likely to be aware. This case report highlights the opposite problem, where the monitor (M-Entropy) indicated an awake state but the patient was in fact deeply anaesthetised. If the anaesthetist is unable to interpret the raw electroencephalogram and understand the limitations of the monitor being used, excessive doses of anaesthetic may be given with potentially serious consequences.