General Anesthetic Agents Research Articles

Instantaneous 3D EEG Signal Analysis Based on Empirical Mode Decomposition and the Hilbert–Huang Transform Applied to Depth of Anaesthesia

Depth of anaesthesia (DoA) is an important measure for assessing the degree to which the central nervous system of a patient is depressed by a general anaesthetic agent, depending on the potency and concentration with which anaesthesia is administered during surgery. We can monitor the DoA by observing the patient’s electroencephalography (EEG) signals during the surgical procedure. Typically high frequency EEG signals indicates the patient is conscious, while low frequency signals mean the patient is in a general anaesthetic state. If the anaesthetist is able to observe the instantaneous frequency changes of the patient’s EEG signals during surgery this can help to better regulate and monitor DoA, reducing surgical and post-operative risks. This paper describes an approach towards the development of a 3D real-time visualization application which can show the instantaneous frequency and instantaneous amplitude of EEG simultaneously by using empirical mode decomposition (EMD) and the Hilbert–Huang transform (HHT). HHT uses the EMD method to decompose a signal into so-called intrinsic mode functions (IMFs). The Hilbert spectral analysis method is then used to obtain instantaneous frequency data. The HHT provides a new method of analyzing non-stationary and nonlinear time series data. We investigate this approach by analyzing EEG data collected from patients undergoing surgical procedures. The results show that the EEG differences between three distinct surgical stages computed by using sample entropy (SampEn) are consistent with the expected differences between these stages based on the bispectral index (BIS), which has been shown to be quantifiable measure of the effect of anaesthetics on the central nervous system. Also, the proposed filtering approach is more effective compared to the standard filtering method in filtering out signal noise resulting in more consistent results than those provided by the BIS. The proposed approach is therefore able to distinguish between key operational stages related to DoA, which is consistent with the clinical observations. SampEn can also be viewed as a useful index for evaluating and monitoring the DoA of a patient when used in combination with this approach.

Electroconvulsive therapy in mood diorders

Electroconvulsive therapy (ECT) is one of the less used somatic treatments in mood disorders, especially depressive phase. ECT use has importance during acute bipolar episode when patient extremely violent, suicidal and extreme psychomotor retardation. The aim of this study was to know about socio-demographic profile and therapeutic efficacy of the use of ECT in mood disorders. Methods: This is a prospective comparative study between patients who received ECT and who did not. Psychopathology was evaluated using Young Mania Rating Scale (YMRS) and Hamilton Depression Rating Scale (HDRS) between the groups at admission, at discharge, at 1st month, at 6th month and at 12th month. Modified ECT was performed using general anesthetic agent. Results: Twenty five patients received ECT as compared to 32 patients who were non-receivers. There was significant decrease in HDRS in ECT receiver as compared to non-receivers in patients with depression (both unipolar and bipolar) at discharge, 1st month, and 12th month; in YMRS in patient with mania at discharge, 1st month and at 12th month.Discussion: There was significant improvement in overall psychopathology and psycho-social status of patients who received ECT as compared to non-receivers. The improvement was shown by decrement in scores in HDRS and YMRS at the time of discharge, 1st month, 6th month and 1st year which were statistically significant.DOI: http://dx.doi.org/10.3126/jcmc.v4i4.11958

Anesthesia in the Surgery of Strabismus: Role of Anesthetic Agents in the Ocular Deviation and Surgical Outcome

Purpose: To determine whether the changes in the ocular alignment following general anesthesia, maintained with two different inhalational anesthetic agents, sevoflurane and desflurane, can be used as a predictor for surgical outcomes in children with esotropia. Methods: The authors obtained digital photographs of 42 children with esotropia; 21 patients underwent strabismus surgery with general inhalation anesthesia with sevoflurane (group A), 21 patients with inhalatory anesthesia with desflurane (Group B), as maintenance general anesthesia agents. For each patient, the corneal reflexes position were digitally measured and compared with the preoperative ocular deviation’s angle; the correlation with surgical outcome, one year after, was considered. Results: The patients in both groups showed a decrease of the squint angle, or eye’s gap position after the induction of general anesthesia. In group B, this divergence was significantly higher than in group A (P 1 SD. Conclusion: Changes in the ocular deviation with sevoflurane and desflurane, can be predictive for surgery outcome in children with esotropia. Furthermore, desflurane evidenced greater effects on the ocular deviation compared to sevoflurane, thus confirming to be the inhalational anesthetic of choice in strabismus surgery.

The intracarotid etomidate Wada test: A 54-patient series

Hemispheric language dominance and isolated hemispheric memory function evaluation can be undertaken with the intracarotid injection of a general anesthetic agent (Wada test). Amobarbital has been traditionally used as the anesthetic agent, but legal and commercial constraints limit its use. We evaluated the use of etomidate as an alternative agent for the Wada test in a series of 54 consecutive adult patients with mesial temporal sclerosis undergoing presurgical evaluation for epilepsy surgery. Language lateralization and hemispheric memory function evaluation were successfully achieved in all cases. Side effects (somnolence, tremor, and dystonia) were infrequent, minor, and transient and did not require interruption of the procedure. Etomidate appears to be a safe and effective alternative agent to amobarbital in the Wada test. Similarly to the amobarbital Wada test, the ability of the etomidate Wada test to predict postoperative memory decline remains unclear.

Effects of sevoflurane versus other general anaesthesia on emergence agitation in children.

Effects of sevoflurane versus other general anaesthesia on emergence agitation in children.

Propofol selectively alters GluA1 AMPA receptor phosphorylation in the hippocampus but not prefrontal cortex in young and aged mice

Propofol is a commonly used general anesthetic agent which has been previously shown to enhance the inhibitory GABAergic transmission in the central nervous system. In addition to the GABAergic element, the excitatory transmission may be another central molecular site impacted by propofol. Increasing evidence implies that the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor represents an excitatory amino acid receptor subtype subjected to the regulation by propofol. Indeed, in this study, we found that a single injection of propofol at an anesthetic dose increased AMPA receptor GluA1 subunit phosphorylation in young (2–3 months old) and aged (20–21 months old) mice in vivo. Propofol caused an increase in GluA1 phosphorylation in the hippocampus but not in the prefrontal cortex. The propofol effect was also site-selective as the drug elevated GluA1 phosphorylation at serine 831 (S831) but not serine 845. Interestingly, while propofol induced a moderate and transient increase in S831 phosphorylation in young mice, the drug caused a substantial and sustained S831 phosphorylation in aged animals. Total GluA1 abundance remained stable in the hippocampus and prefrontal cortex in both young and aged mice in response to propofol. These results provide evidence supporting the sensitivity of GluA1 AMPA receptors to propofol. A single dose of propofol was able to upregulate GluA1 phosphorylation in the confined hippocampus in an age-dependent manner.

P2 The detection of propofol glucuronide in human hair using LC-MS/MS: Case study and survey of high-risk health professionals

Background Propofol (2,6-diisopropylphenol) is a commonly used agent for general anesthesia because of its short duration, quick recovery time, and minimal side effects. Although not a controlled substance in the United States, propofol abuse and misuse by medical professionals has increased 5-fold between 1997 and 2011. Propofol detection in biological fluids has a very short detection window and the presence of propofol in hair does not distinguish between ingestion and environmental exposure. A metabolite, propofol glucuronide, is formed in the liver and may be detected in the hair. The purpose of this study is to validate a method for the detection of propofol glucuronide in hair and apply this method to a case study and a survey of high-risk health professionals. Methods A method for the detection of propofol glucuronide was developed and validated according commonly recognized guidelines. Briefly, hair specimens were powdered and extracted into water while incubating in a sonicating water batch without heat over night. Extracts were subjected to solid phase extraction using quaternary amine with chloride counter ion extraction cartridges. The eluates were evaporated under nitrogen at 40 °C, reconstituted in 100 μL of DI water. Extracts were separated using Synergy Polar RP column (50mm x 2mm x 2.5 μm particle size) on an Agilent 1200 HPLC system. The compounds were detected on an AB Sciex 5500 tandem mass spectrometer (LC-MS/MS) following the transitions of 353,1 m/z to 176,7 m/z , 112,6 m/z , 84,7 m/z for propofol glucuronide and 370,1 m/z to 193,7 m/z and 369,7 m/z for the internal standard, propofol glucuronide- d 17 . A hair specimen that originated from a 50 year old woman that was anesthetized for 15 minutes was analyzed. Additionally, a survey of 300 de-identified hair specimen remnants that originated from health professionals undergoing treatment for substance abuse. Results The empirically determined LOD and LOQ for this assay were 4 pg/mg and 8 pg/mg, respectively. The intra- and inter-assay bias and imprecision studies were all acceptable ( Conclusion This method demonstrated sufficient precision, accuracy and robustness with an analytical measurement range between 8 pg/mg and 100 pg/mg. While being sensitive enough to identify two individuals in a survey of high-risk substance abuse treatment participants, the method was not able to identify propofol metabolite in the hair of a woman receiving a routine quantity of propofol administered during a short surgical procedure. This method provides substance abuse treatment professionals with another objective tool to identify propofol abusers.

Modulation of a voltage-gated Na+ channel by sevoflurane involves multiple sites and distinct mechanisms.

Halogenated inhaled general anesthetic agents modulate voltage-gated ion channels, but the underlying molecular mechanisms are not understood. Many general anesthetic agents regulate voltage-gated Na(+) (NaV) channels, including the commonly used drug sevoflurane. Here, we investigated the putative binding sites and molecular mechanisms of sevoflurane action on the bacterial NaV channel NaChBac by using a combination of molecular dynamics simulation, electrophysiology, and kinetic analysis. Structural modeling revealed multiple sevoflurane interaction sites possibly associated with NaChBac modulation. Electrophysiologically, sevoflurane favors activation and inactivation at low concentrations (0.2 mM), and additionally accelerates current decay at high concentrations (2 mM). Explaining these observations, kinetic modeling suggests concurrent destabilization of closed states and low-affinity open channel block. We propose that the multiple effects of sevoflurane on NaChBac result from simultaneous interactions at multiple sites with distinct affinities. This multiple-site, multiple-mode hypothesis offers a framework to study the structural basis of general anesthetic action.

Anesthesia and evoked responses in neurosurgery.

Anesthesia and evoked responses in neurosurgery.

Midazolam as an induction agent in comparison with propofol as a safe and effective alternative

Introduction: Propofol produce rapid and smooth induction of anesthesia, with rapid metabolism, which would allow it to be used for the maintenance of anesthesia and free from the risk of anaphylactic reactions. Midazolam a new short acting water soluble Benzodiazepine with cardio vascular effects similar to that of diazepam may be an effective alternative for induction of anesthesia. Methods: In this randomized study, all together 48 patients undergoing various surgical procedures belonging to Orthopedic, General Surgery and Gynecological Surgeries constituted the study group. Group-I (Midazolam Group) received intra-venous Midazolam 0.15mg/Kg for induction of anesthesia and Group-II (Propofol Group) received 2mg/kg intravenous Propofol for Induction of Anesthesia. Induction time, Heart Rate, Non invasive blood Pressure is recorded at 1minute interval for 5 minutes and after that at an interval for 5 minutes for another 30 minutes. Demographic data was analyzed by Student’s t-test. Results: The study showed no statistical significance in hemodynamic responses with either Midazolam or Propofol as an induction agent for General Anesthesia but there was statistically difference with respect to heart rate (P=0.001). Conclusion: Midazolam was proven effective compared to Propofol as an induction Agent. DOI: http://dx.doi.org/10.3126/joim.v34i1.9119 Journal of Institute of Medicine, April, 2012; 34:1 25-32

Modulation of Functional EEG Networks by the NMDA Antagonist Nitrous Oxide

Parietal networks are hypothesised to play a central role in the cortical information synthesis that supports conscious experience and behavior. Significant reductions in parietal level functional connectivity have been shown to occur during general anesthesia with propofol and a range of other GABAergic general anesthetic agents. Using two analysis approaches (1) a graph theoretic analysis based on surrogate-corrected zero-lag correlations of scalp EEG, and (2) a global coherence analysis based on the EEG cross-spectrum, we reveal that sedation with the NMDA receptor antagonist nitrous oxide (N2O), an agent that has quite different electroencephalographic effects compared to the inductive general anesthetics, also causes significant alterations in parietal level functional networks, as well as changes in full brain and frontal level networks. A total of 20 subjects underwent N2O inhalation at either 20%, 40% or 60% peak N2O/O2 gas concentration levels. N2O-induced reductions in parietal network level functional connectivity (on the order of 50%) were exclusively detected by utilising a surface Laplacian derivation, suggesting that superficial, smaller spatial scale, cortical networks were most affected. In contrast reductions in frontal network functional connectivity were optimally discriminated using a common-reference derivation (reductions on the order of 10%), indicating that the NMDA antagonist N2O induces spatially coherent and widespread perturbations in frontal activity. Our findings not only give important weight to the idea of agent invariant final network changes underlying drug-induced reductions in consciousness, but also provide significant impetus for the application and development of multiscale functional analyses to systematically characterise the network level cortical effects of NMDA receptor related hypofunction. Future work at the source space level will be needed to verify the consistency between cortical network changes seen at the source level and those presented here at the EEG sensor space level.

Determination of ketamine and norketamine in hair by micropulverized extraction and liquid chromatography–high resolution mass spectrometry

Ketamine (KT), primarily used as a general anaesthetic agent in clinical practice, has become very popular in recent years as a recreational drug, due to its dissociative and hallucinogenic effects. A liquid chromatography-high resolution mass spectrometry (LC–HRMS) method has been developed and validated for the quantification of KT and its main metabolite norketamine (NK) in 2.0mg of hair. Sample preparation consisted of a rapid, simultaneous pulverization and extraction step in acidic solution, followed by centrifugation and filtration. Gradient elution was performed by an Atlantis T3 analytical column, and deuterated KT was used as the internal standard. Positive ion electrospray ionization and HRMS determination in full-scan mode were achieved with an Orbitrap mass spectrometer. The method has a linear range of 0.05–50ng/mg, a limit of quantisation of 0.05ng/mg and a limit of detection of 0.02ng/mg for both KT and NK. The validated method was applied for the determination of KT and NK in two authentic hair samples from subjects suspected of taking psychoactive substances. The detection of the metabolite at low concentration gave proof for systemic drug origin and an investigation into the possible presence of further metabolites was performed by means of retrospective screening.

Evaluation of Propofol as a General Anesthetic Agent for Minor Oral Surgical Procedure

Nausea and vomiting following anesthesia is a distressing problem for the patient as it increases the recovery time, intensity of nursing care and delays discharge. The aim of randomized controlled single blind study is to evaluate the efficacy and safety of subhypnotic doses of propofol for the prevention of postoperative nausea and vomiting (PONV) in day care management of cases in oral and maxillofacial surgeries. Twenty-five patient of ASA-1 with age ranging from 12 to 40 years were scheduled for various maxillofacial surgical cases like fracture, cyst enucleation, surgical removal of 3rd molar, etc. were given propofol at the dose of 2 to 2.5 mg/kg as induction dose and sedation was maintained with the dose 5 to 10 mg/min. There was no significant effect on heart rate, systolic and diastolic blood pressure, respiratory rate and oxygen saturation intraoperatively. In conclusion, a subhypnotic dose of propofol is fast acting, safe and easily controllable, short acting general anesthetic agent with rapid recovery. The study found that the PONV was significantly reduced in the patient with propofol, no hemodynamic derangements were noted in the postoperative period.

Ketamine, Propofol, and the EEG: A Neural Field Analysis of HCN1-Mediated Interactions

Ketamine and propofol are two well-known, powerful anesthetic agents, yet at first sight this appears to be their only commonality. Ketamine is a dissociative anesthetic agent, whose main mechanism of action is considered to be N-methyl-d-aspartate (NMDA) antagonism; whereas propofol is a general anesthetic agent, which is assumed to primarily potentiate currents gated by γ-aminobutyric acid type A (GABAA) receptors. However, several experimental observations suggest a closer relationship. First, the effect of ketamine on the electroencephalogram (EEG) is markedly changed in the presence of propofol: on its own ketamine increases θ (4–8 Hz) and decreases α (8–13 Hz) oscillations, whereas ketamine induces a significant shift to beta band frequencies (13–30 Hz) in the presence of propofol. Second, both ketamine and propofol cause inhibition of the inward pacemaker current Ih, by binding to the corresponding hyperpolarization-activated cyclic nucleotide-gated potassium channel 1 (HCN1) subunit. The resulting effect is a hyperpolarization of the neuron’s resting membrane potential. Third, the ability of both ketamine and propofol to induce hypnosis is reduced in HCN1-knockout mice. Here we show that one can theoretically understand the observed spectral changes of the EEG based on HCN1-mediated hyperpolarizations alone, without involving the supposed main mechanisms of action of these drugs through NMDA and GABAA, respectively. On the basis of our successful EEG model we conclude that ketamine and propofol should be antagonistic to each other in their interaction at HCN1 subunits. Such a prediction is in accord with the results of clinical experiment in which it is found that ketamine and propofol interact in an infra-additive manner with respect to the endpoints of hypnosis and immobility.

Propofol induced severe neuroexcitatory symptoms during emergency laparotomy

Propofol is a widely used intravenous agent for general anesthesia and sedation. Propofol is associated with a variety of neuroexcitatory events including: opisthotonus, muscle rigidity, myoclonus, and seizures collectively termed as seizure-like phenomenon (SLP). We report a rare case of propofol induced severe neuroexcitatory symptoms at the time of induction in a young male presenting for emergency laparotomy. He developed generalized tonic- clonic seizures which resulted in dislodgement of intravenous cannula. Immediately a new intravenous cannula was inserted with difficulty during convulsions and injection thiopentone 200 mg bolus was given. Convulsions subsided within a minute. Patient remained hemodynamically stable and surgery was uneventful. He developed emergence agitation which was treated with injection midazolam. Patient recovered with no neurologic sequelae.

Long-term psychosocial behavioral outcomes in children following anesthesia: A comparison of the effects of general versus regional anesthesia on term infants delivered by elective cesarean section

Background: Data on the effects of general anesthesia on the fetal and neonatal brain are limited. Animal studies demonstrated that anesthetic agents leave their consequences in the form of learning and memory deficits. The effects of propofol on the fetal neurodevelopment are not clear yet. Materials and Methods: This is a telephone-based questionnaire survey that addressed the effect of general anesthesia by propofol during cesarean section at term with no perinatal complications on the psychosocial behavior of children at 8-10 years of age compared with children having same characteristics except for delivery under neuraxial anesthesia using the Pediatric Symptom Checklist as a score. Results: A total of 187 children were born at term between January 1, 2002 and December 31, 2004 with no perinatal distress under induction of general anesthesia by propofol. 66 children (35.3%) were lost to follow-up and parents of two children (1.1%) refused to participate. A total of 189 children were included in the study: 119 were born by cesarean section under general anesthesia and 70 were born by cesarean section under neuraxial block. The incidence of psychosocial behavior impairment at 8-10 years of age was not found to be affected by the mode of anesthesia during delivery by cesarean section nor by neonatal nor parental characteristics. Conclusion: Exposure to propofol as an induction agent for general anesthesia or cesarean section does not seem to increase the psychosocial behavior disorder development risk at 8-10 years of age.

A study of psycho-behavioral patterns in patients emerging from general anesthesia using sevoflurane, propofol and their combination in early, intermediate and late post-operative period: A randomized controlled trial.

Background:It has been contended the general anesthetic agents also may affect the psycho-social behavior of the patients, especially during the emergence from GA. This assumes much significance in day cases where, patients have to be roadworthy and mentally stable before discharge.Aims:We compared the psycho-behavioral effects of propofol, sevoflurane and their combination, while emerging from anesthesia.Settings and Design:The patients coming for short duration day care anesthesia were studied in a prospective randomized controlled comparison.Materials and Methods:The psycho-behavioral changes in early, intermediate and late recovery period were studied in 60 consenting patients undergoing Total Intra Venous Anesthesia (TIVA) using Propofol, Volatile Induction and Maintenance Anesthesia (VIMA) using Sevoflurane and the combination of these two agents.Statistical Analysis:Statistical Analysis of the data and application of various statistical tests was carried out with help of Statistical Package for Social Services (SPSS version 18). Data were compiled, analyzed and presented as frequency, proportions, mean and standard deviation. The tests of significance, like Chi-square test, percentages, independent sample t test, paired t test, and P value were used in the study.Results and Conclusions:Both the modalities of GA, viz; TIVA and VIMA, do produce significant psycho-behavioral changes in the patients after GA, though transiently. So it is imperative for the Clinicians to anticipate the entire aspect of Psycho-behavioral patterns before discharging the day cases from the Post anesthesia Care Unit (PACU).

Critical Regulation of Calcium Signaling and NMDA-type Glutamate Receptor In Developmental Neural Toxicity

Calcium (Ca 2+ ) is a vital element in the process of neurotransmitter release, and is a common signaling mechanism. Calcium can act in signal transduction after influx resulting from activation of ion channels or as a second messenger. Glutamate receptors play an important role in the excitatory synaptic action of the central nervous system. Activation of the N-methyl-D-aspartate (NMDA)-type glutamate receptor increases the concentration of (Ca 2+ ) in the cell. Ca 2+ can in turn function as a second messenger in various signaling pathways. The developing nervous system varies in susceptibility to neurotoxic insults depending on the stage of development. By monitoring alterations in calcium influx, cell signaling processes, expression levels of receptor subtypes and imaging outcomes, it may be possible to completely define the affected system(s) during development. This review attempts to discuss how the potential application of some sophisticated research approaches, e.g., calcium imaging/Ca 2+ influx and monitoring gene and/or protein expression levels of receptor subtypes, provides a platform in which preclinical research models can inform clinical interventions and vice versa in the developing brain. This review focuses the discussion on representative general anesthetic agents - primarily ketamine - as examples of how the Ca 2+ influx event and specific receptor subunit expression can be used to dissect relevant mechanisms underlying the etiology of the neurotoxicity associated with developmental exposures to anesthetic agents.

Anesthesia and Alzheimer's disease: time to wake up!

It has long been observed that some patients suffer a significant cognitive impact following anesthesia and surgery. This should not be surprising when considering that not only is the target organ for general anesthetic agents the brain itself but also that the process of anesthesia is a form of deep, pharmacologically induced coma rather than “sleep.” The expectation that such a process should be fully reversible with transient neurophysiological effects contradicts our experience with repeated abuse of other central nervous system depressants such as glue, petrol, and alcohol. Of great concern is that, while approximately 10% of populations in developed countries undergo anesthesia and surgery of some form each year, the proportion of the elderly making up this group is much greater. In addition, it is the elderly who are potentially at a greater risk of cognitive impairment following such procedures because many have decreased cognitive reserve, either due to pre-existing mild cognitive impairment (MCI) or frank dementia, which may be diagnosed or unknown. The impact of anesthesia on these individuals is poorly understood, as are the implications of the emerging laboratory data that suggest an effect of anesthetic agents on the pathological processes of Alzheimer's Disease (AD) itself.

Anesthetics Interfere With the Polarization of Developing Cortical Neurons

Numerous studies from the clinical and preclinical literature indicate that general anesthetic agents have toxic effects on the developing brain, but the mechanism of this toxicity is still unknown. Previous studies have focused on the effects of anesthetics on cell survival, dendrite elaboration, and synapse formation, but little attention has been paid to possible effects of anesthetics on the developing axon. Using dissociated mouse cortical neurons in culture, we found that isoflurane delays the acquisition of neuronal polarity by interfering with axon specification. The magnitude of this effect is dependent on isoflurane concentration and exposure time over clinically relevant ranges, and it is neither a precursor to nor the result of neuronal cell death. Propofol also seems to interfere with the acquisition of neuronal polarity, but the mechanism does not require activity at GABAA receptors. Rather, the delay in axon specification likely results from a slowing of the extension of prepolarized neurites. The effect is not unique to isoflurane as propofol also seems to interfere with the acquisition of neuronal polarity. These findings demonstrate that anesthetics may interfere with brain development through effects on axon growth and specification, thus introducing a new potential target in the search for mechanisms of pediatric anesthetic neurotoxicity.