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For this child, at this particular moment, how much anesthesia should I give? Determining the drug requirements of a specific patient is a fundamental problem in medicine. Our current approach uses population-based pharmacological models to establish dosing. However, individual patients, and children in particular, may respond to drugs differently. In anesthesiology, we have the advantage that we can monitor our patients in real time and titrate drugs to the desired effect. Examples include blood pressure management or muscle relaxation. Although the brain is the primary site of action for sedative-hypnotic drugs, the brain is not routinely monitored during general anesthesia or sedation, a fact that would surprise many patients. One reason for this is that, until recently, physiologically principled approaches for anesthetic brain monitoring have not been articulated. In the past few years, our knowledge of anesthetic brain mechanisms has developed rapidly. We now know that anesthetic drug effects are clearly visible in the electroencephalogram (EEG) of adults and reflect underlying anesthetic pharmacology and brain mechanisms. Most recently, similar effects have been characterized in children. In this article, we describe how EEG monitoring could be used to guide anesthetic management in pediatric patients. We review previous evidence and present multiple case studies showing how drug-specific and dose-dependent EEG signatures seen in adults are visible in children and infants, including those with neurological disorders. We propose that the EEG can be used in the anesthetic care of children to enable anesthesiologists to better assess the drug requirements of individual patients in real time and improve patient safety and experience.

Over the past few decades, there have been many advances in pediatric surgery, some using new devices (eg, VEPTR, MAGEC rods) and others using less invasive approaches (eg, Nuss procedure, endoscopic cranial suture release, minimally invasive tethered cord release). Although many of these procedures were initially met with caution or skepticism, continued experience over the past few decades has shown that these procedures are safe and effective. This article reviews the anesthetic considerations for these conditions and procedures.

BACKGROUND Few studies have systematically described relationships between clinical–behavioural signs, electroencephalographic (EEG) patterns and age during emergence from anaesthesia in young children. OBJECTIVE To identify the relationships between end-tidal sevoflurane (ETsevoflurane) concentration, age and frontal EEG spectral properties in predicting recovery of clinical–behavioural signs during emergence from sevoflurane in children 0 to 3 years of age, with and without exposure to nitrous oxide. The hypothesis was that clinical signs occur sequentially during emergence, and that for infants aged more than 3 months, changes in alpha EEG power are correlated with clinical–behavioural signs. DESIGN An observational study. SETTING A tertiary paediatric teaching hospital from December 2012 to August 2016. PATIENTS Ninety-five children aged 0 to 3 years who required surgery below the neck. OUTCOME MEASURES Time–course of, and ETsevoflurane concentrations at first gross body movement, first cough, first grimace, dysconjugate eye gaze, frontal (F7/F8) alpha EEG power (8 to 12 Hz), frontal beta EEG power (13 to 30 Hz), surgery-end. RESULTS Clinical signs of emergence followed an orderly sequence of events across all ages. Clinical signs occurred over a narrow ETsevoflurane, independent of age [movement: 0.4% (95% confidence interval (CI), 0.3 to 0.4), cough 0.3% (95% CI, 0.3 to 0.4), grimace 0.2% (95% CI, 0 to 0.3); P > 0.5 for age vs. ETsevoflurane]. Dysconjugate eye gaze was observed between ETsevoflurane 1 to 0%. In children more than 3 months old, frontal alpha EEG oscillations were present at ETsevoflurane 2.0% and disappeared at 0.5%. Movement occurred within 5 min of alpha oscillation disappearance in 99% of patients. Nitrous oxide had no effect on the time course or ETsevoflurane at which children showed body movement, grimace or cough. CONCLUSION Several clinical signs occur sequentially during emergence, and are independent of exposure to nitrous oxide. Eye position is poorly correlated with other clinical signs or ETsevoflurane. EEG spectral characteristics may aid prediction of clinical–behavioural signs in children more than 3 months.

Background Anaesthetic drugs act at sites within the brain that undergo profound changes during typical ageing. We postulated that anaesthesia-induced brain dynamics observed in the EEG change with age. Methods We analysed the EEG in 155 patients aged 18–90 yr who received propofol (n=60) or sevoflurane (n=95) as the primary anaesthetic. The EEG spectrum and coherence were estimated throughout a 2 min period of stable anaesthetic maintenance. Age-related effects were characterized by analysing power and coherence as a function of age using linear regression and by comparing the power spectrum and coherence in young (18- to 38-yr-old) and elderly (70- to 90-yr-old) patients. Results Power across all frequency bands decreased significantly with age for both propofol and sevoflurane; elderly patients showed EEG oscillations ∼2- to 3-fold smaller in amplitude than younger adults. The qualitative form of the EEG appeared similar regardless of age, showing prominent alpha (8–12 Hz) and slow (0.1–1 Hz) oscillations. However, alpha band dynamics showed specific age-related changes. In elderly compared with young patients, alpha power decreased more than slow power, and alpha coherence and peak frequency were significantly lower. Older patients were more likely to experience burst suppression. Conclusions These profound age-related changes in the EEG are consistent with known neurobiological and neuroanatomical changes that occur during typical ageing. Commercial EEG-based depth-of-anaesthesia indices do not account for age and are therefore likely to be inaccurate in elderly patients. In contrast, monitoring the unprocessed EEG and its spectrogram can account for age and individual patient characteristics.

Background: General anaesthetics generate spatially defined brain oscillations in the EEG that relate fundamentally to neural-circuit architecture. Few studies detailing the neural-circuit activity of general anaesthesia in children have been described. The study aim was to identify age-related changes in EEG characteristics that mirror different stages of early human brain development during sevoflurane anaesthesia. Methods: Multichannel EEG recordings were performed in 91 children aged 0–3 yr undergoing elective surgery. We mapped spatial power and coherence over the frontal, parietal, temporal, and occipital cortices during maintenance anaesthesia. Results: During sevoflurane exposure: (i) slow–delta (0.1–4 Hz) oscillations were present in all ages, (ii) theta (4–8 Hz) and alpha (8–12 Hz) oscillations emerge by ∼4 months, (iii) alpha oscillations increased in power from 4 to 10 months, (iv) frontal alpha-oscillation predominance emerged at ∼6 months, (v) frontal slow oscillations were coherent from birth until 6 months, and (vi) frontal alpha oscillations became coherent ∼10 months and persisted in older ages. Conclusions: Key developmental milestones in the maturation of the thalamo-cortical circuitry likely generate changes in EEG patterns in infants undergoing sevoflurane general anaesthesia. Characterisation of anaesthesia-induced EEG oscillations in children demonstrates the importance of developing age-dependent strategies to monitor properly the brain states of children receiving general anaesthesia. These data have the potential to guide future studies investigating neurodevelopmental pathologies involving altered excitatory–inhibitory balance, such as epilepsy or Rett syndrome., National Institutes of Health (Grants R01-GM104948 and DP1-OD003646 and DP2- OD006454)

The general anesthetic sevoflurane acts on GABAergic-interneurons to generate stereotyped oscillations that relate fundamentally to neural circuit architecture. Each year, millions of children require general anesthesia, providing an experiment of nature that allows characterization of the developmental trajectory of GABAergic-inhibitory circuits in the human brain. We used multichannel electroencephalograph recordings in 91 children 0-40 months old. We mapped spatial power and coherence across the cortex. During sevoflurane exposure: (1) slow-delta oscillations are present in all ages; (2) theta and alpha oscillations emerge around 4 months; (3) alpha oscillations increase in power from 4 to 10 months; (4) frontal alpha oscillation predominance emerge at ~6 months; (5) frontal slow oscillations are coherent in the first 6 months of age only; and (6) frontal alpha oscillations become coherent around 10 months and persist in older ages. Our results suggest key developmental milestones are visible in the functional activity of sevoflurane-stimulated GABAergic circuits.

BackgroundIn adults, frontal electroencephalogram patterns observed during propofol-induced unconsciousness consist of slow oscillations (0.1 to 1 Hz) and coherent alpha oscillations (8 to 13 Hz). Given that the nervous system undergoes significant changes during development, anesthesia-induced electroencephalogram oscillations in children may differ from those observed in adults. Therefore, we investigated age-related changes in frontal electroencephalogram power spectra and coherence during propofol-induced unconsciousness.MethodsWe analyzed electroencephalogram data recorded during propofol-induced unconsciousness in patients between 0 and 21 yr of age (n = 97), using multitaper spectral and coherence methods. We characterized power and coherence as a function of age using multiple linear regression analysis and within four age groups: 4 months to 1 yr old (n = 4), greater than 1 to 7 yr old (n = 16), greater than 7 to 14 yr old (n = 30), and greater than 14 to 21 yr old (n = 47).ResultsTotal electroencephalogram power (0.1 to 40 Hz) peaked at approximately 8 yr old and subsequently declined with increasing age. For patients greater than 1 yr old, the propofol-induced electroencephalogram structure was qualitatively similar regardless of age, featuring slow and coherent alpha oscillations. For patients under 1 yr of age, frontal alpha oscillations were not coherent.ConclusionsNeurodevelopmental processes that occur throughout childhood, including thalamocortical development, may underlie age-dependent changes in electroencephalogram power and coherence during anesthesia. These age-dependent anesthesia-induced electroencephalogram oscillations suggest a more principled approach to monitoring brain states in pediatric patients.

Summary The tests reported here relate to the disclosure not only of additional stocks of mice that were found to be resistant to the development of acute disseminated encephalomyelitis, such as the Webster BRVR and BRVS stocks, but also to other stocks that were partially susceptible, namely the Webster BSVR and C3H mice, and to still another breed, the Webster BSVS that was fully susceptible. Of the proteolipide “A + B” fraction of mouse or cattle CNS tissues, the “A” moiety was active and the “B” inactive after their inoculation into mice and guinea pigs. The bovine proteolipide “C” component was found to be inactive in these animals. Effective production of encephalomyelitis in the mouse followed only when a Freund-type adjuvant was mixed with central nervous system tissue materials and injected as a mixture. In mice that have responded with development of encephalomyelitis and then remitted to a quiescent state, the injection into them of mouse brain alone brought out an immediate reaction of hypersensitivity. A discussion is included on the variations occurring in experimental reactions to the materials, methods, and animals employed for the production of the encephalomyelitis, and the relation of hypersensitivity to its development.

The susceptibility of homozygous BSVS mice to acute disseminated encephalomyelitis (ADE) has been found to be nutritionally dependent. On a laboratory stock regimen of commercial fox chow pellets, whole wheat bread, and milk this genotype is 100 per cent susceptible to the disease. On a "synthetic" diet, containing a minimal list of vitamins adequate for growth and maintenance, susceptibility was found to be reduced to 15 per cent. Supplementation of the "synthetic" diet with biotin, folic acid, and vitamin B12 restored susceptibility to a frequency of 70 per cent. Increasing the supplements tenfold had no further effect in restoring susceptibility frequencies to the 100 per cent level. In the restoration of susceptibility, folic acid and vitamin B12 were equally effective as single supplements and equivalent to the triple vitamin supplement. The effect of single biotin supplementation was less. An outbreak of fatal pasteurellosis among BSVS mice latently infected with Pasteurella and used in an ADE susceptibility test has been described. The fatal pasteurellosis has been ascribed to a constellation of determinants including (a) diet, (b) sex, (c) inoculation events, and (d) latent infection with Pasteurella. With males the susceptible sex it was possible to avert the fatal pasteurellosis and continue the nutritional experiments by using females exclusively.

ConclusionBy manipulations here described it was possible to induce acute disseminated encephalomyelitis in mice in a shorter time than heretofore, with fewer inoculations and with uniform response. The improved method consists of the intraperitoneal injection of H. pertussis vaccine followed by 2 spaced intracutaneous injections of proteolipide A + B prepared in a Freund-type adjuvant.

The production of EAE in the fully susceptible BSVS mouse genotype has been found to be dependent on the ratio of proteolipid antigen and adjuvant mycobacterial concentration as used in the emulsion, of the Freund type. Disturbance of this ratio, by manipulation of either component, by diminution or increase, results in a decrease in the frequency by which EAE is produced. Simultaneous reduction of antigen and mycobacteria, so that the ratio remains unchanged, retains the full EAE-producing power of the emulsion. The limit of this has not been ascertained. Emulsifying agents have been found to restrict further the permissible limits of the antigen-mycobacterial ratio for full EAE production. Such effects of the emulsifier have been found to vary with the qualitative nature of the emulsifier. Aquaphor has been found to be less restrictive than falba. These phenomena, systematically analyzed here for the mouse, may have an application for other antigen-adjuvant systems and for other hosts.

ConclusionsAn examination of 4 lines of inbred mice for susceptibility to experimental acute disseminated encephalomyelitis revealed a resistant line, BRVR, and a susceptible line, BSVS. The simplest explanation of the data here presented is that the 2 appear to differ by two resistance-conferring genetic factors either of which is adequate to bring about resistance.

Susceptible (BSVS) and resistant (BRVR) mice were experimentally infected with Salmonella typhimurium. The double strain inoculation technique was used in which both avirulent and virulent representatives of S. typhimurium were admitted into the hosts. The BSVS mice succumbed without exception while the BRVR mice survived to 52 per cent. No deaths occurred during the experimental period in non-infected control mice. Parallel to the survivorship test, and concurrent with it, the activity of the reticulo-endothelial system (RES) was measured at frequent intervals in identically infected BSVS and BRVR mice and in their non-infected controls. For this measurement the carbon clearance method was used. No pre-infection difference of activity of the RES could be discerned in susceptible BSVS mice vs. resistant BRVR. Following infection, increases in the RES activity were detected in about the same magnitude in both mouse stocks. However, a difference was found in the time of onset. The susceptible animals showed an early and short increase in the activity of the RES, followed by a drop to control levels at the time of death. The resistant group exhibited a considerably delayed, but significant increase in RES activity, which returned to control levels approximately 4 weeks after infection. The absolute white blood count did not undergo significant change in either of the two infected groups, but the susceptible animals showed a relative increase of their neutrophils at the expense of their lymphocytes. Extensive anatomical changes were observed in both mouse strains, mainly confined to liver and spleen. These consisted of stasis, swelling of Kupffer cells, necrotic foci, histiocytic-monocytic nodules, widespread thrombosis of branches of the portal and splenic veins, and extensive areas of necrosis. These changes appeared earlier in susceptible than in resistant animals. The implications of these findings are discussed.

THE pathogenesis of experimental allergic encephalomyelitis (EAE) is not definitely known and yet it is frequently used as an experimental model for the study of autoimmune disease of the central nervous system. Waksman contends that the principal event giving rise to EAE after injection of the antigen is the passage of immunologically competent cells or histiocytes through small venules into the nervous system1. These cells originate in the blood stream and are held responsible for the destruction of elements containing antigen in the central nervous system by an undefined mechanism. It has been found that EAE can be suppressed, either by generalized physical or chemical cytotoxic agents, or by destruction of the regional lymph nodes draining the inoculation site2–9. This communication reports the suppressive effect of localized irradiation of the brain in mice during the induction of EAE, and compares the effect with that of total body irradiation.