Anthony Absalom

Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): an international multicentre, randomised controlled trial

__Background__ In laboratory animals, exposure to most general anaesthetics leads to neurotoxicity manifested by neuronal cell death and abnormal behaviour and cognition. Some large human cohort studies have shown an association between general anaesthesia at a young age and subsequent neurodevelopmental deficits, but these studies are prone to bias. Others have found no evidence for an association. We aimed to establish whether general anaesthesia in early infancy affects neurodevelopmental outcomes. __Methods__ In this international, assessor-masked, equivalence, randomised, controlled trial conducted at 28 hospitals in Australia, Italy, the USA, the UK, Canada, the Netherlands, and New Zealand, we recruited infants of less than 60 weeks’ postmenstrual age who were born at more than 26 weeks’ gestation and were undergoing inguinal herniorrhaphy, without previous exposure to general anaesthesia or risk factors for neurological injury. Patients were randomly assigned (1:1) by use of a web-based randomisation service to receive either awake-regional anaesthetic or sevoflurane-based general anaesthetic. Anaesthetists were aware of group allocation, but individuals administering the neurodevelopmental assessments were not. Parents were informed of their infants group allocation upon request, but were told to mask this information from assessors. The primary outcome measure was full-scale intelligence quotient (FSIQ) on the Wechsler Preschool and Primary Scale of Intelligence, third edition (WPPSI-III), at 5 years of age. The primary analysis was done on a per-protocol basis, adjusted for gestational age at birth and country, with multiple imputation used to account for missing data. An intention-totreat analysis was also done. A difference in means of 5 points was predefined as the clinical equivalence margin. This completed trial is registered with ANZCTR, number ACTRN12606000441516, and ClinicalTrials.gov, number NCT00756600. __Findings__ Between Feb 9, 2007, and Jan 31, 2013, 4023 infants were screened and 722 were randomly allocated: 363 (50%) to the awake-regional anaesthesia group and 359 (50%) to the general anaesthesia group. There were 74 protocol violations in the awake-regional anaesthesia group and two in the general anaesthesia group. Primary outcome data for the per-protocol analysis were obtained from 205 children in the awake-regional anaesthesia group and 242 in the general anaesthesia group. The median duration of general anaesthesia was 54 min (IQR 41–70). The mean FSIQ score was 99·08 (SD 18·35) in the awake-regional anaesthesia group and 98·97 (19·66) in the general anaesthesia group, with a difference in means (awake-regional anaesthesia minus general anaesthesia) of 0·23 (95% CI –2·59 to 3·06), providing strong evidence of equivalence. The results of the intention-to-treat analysis were similar to those of the per-protocol analysis. __Interpretation__ Slightly less than 1 h of general anaesthesia in early infancy does not alter neurodevelopmental outcome at age 5 years compared with awake-regional anaesthesia in a predominantly male study population.Summary Background There is pre-clinical evidence that general anaesthetics affect brain development. There is mixed evidence from cohort studies that young children exposed to anaesthesia may have an increased risk of poorer neurodevelopmental outcome. This trial aims to determine if GA in infancy has any impact on neurodevelopmental outcome. The primary outcome for the trial is neurodevelopmental outcome at 5 years of age. The secondary outcome is neurodevelopmental outcome at two years of age and is reported here. Methods We performed an international assessor-masked randomised controlled equivalence trial in infants less than 60 weeks post-menstrual age, born at greater than 26 weeks gestational age having inguinal herniorrhaphy. Infants were excluded if they had existing risk factors for neurologic injury. Infants were randomly assigned to awake-regional (RA) or sevoflurane-based general anaesthesia (GA). Web-based randomisation was performed in blocks of two or four and stratified by site and gestational age at birth. The outcome for analysis was the composite cognitive score of the Bayley Scales of Infant and Toddler Development, Third Edition. The analysis was as-per-protocol adjusted for gestational age at birth. A difference in means of five points (1/3 SD) was predefined as the clinical equivalence margin. The trial was registered at ANZCTR, ACTRN12606000441516 and ClinicalTrials.gov, NCT00756600. Findings Between February 2007, and January 2013, 363 infants were randomised to RA and 359 to GA. Outcome data were available for 238 in the RA and 294 in the GA arms. The median duration of anaesthesia in the GA arm was 54 minutes. For the cognitive composite score there was equivalence in means between arms (RA-GA: +0·169, 95% CI −2·30 to +2·64). Interpretation For this secondary outcome we found no evidence that just under an hour of sevoflurane anaesthesia in infancy increases the risk of adverse neurodevelopmental outcome at two years of age compared to RA.

Adrenocortical function in critically ill patients 24 h after a single dose of etomidate.

We compared the effects of single doses of etomidate and thiopentone on adrenocortical function in a randomised controlled clinical trial involving 35 critically ill patients who needed a general anaesthetic. Just before induction of anaesthesia, a baseline blood cortisol sample was taken. Twenty‐four hours later we performed a short adrenocorticotrophic hormone stimulation test. No patient had a low cortisol level (< 160 nmol.l−1) at any time during the study. Baseline, pre‐ACTH and post‐ACTH cortisol levels were similar in the two groups. However, significantly more patients in the etomidate group had an ACTH‐stimulated cortisol increment < 200 nmol.l−1. The clinical significance of these findings is not clear, but we conclude that single doses of etomidate may interfere with cortisol synthesis for at least 24 h in the critically ill.

Dissociating speech perception and comprehension at reduced levels of awareness.

We used functional MRI and the anesthetic agent propofol to assess the relationship among neural responses to speech, successful comprehension, and conscious awareness. Volunteers were scanned while listening to sentences containing ambiguous words, matched sentences without ambiguous words, and signal-correlated noise (SCN). During three scanning sessions, participants were nonsedated (awake), lightly sedated (a slowed response to conversation), and deeply sedated (no conversational response, rousable by loud command). Bilateral temporal-lobe responses for sentences compared with signal-correlated noise were observed at all three levels of sedation, although prefrontal and premotor responses to speech were absent at the deepest level of sedation. Additional inferior frontal and posterior temporal responses to ambiguous sentences provide a neural correlate of semantic processes critical for comprehending sentences containing ambiguous words. However, this additional response was absent during light sedation, suggesting a marked impairment of sentence comprehension. A significant decline in postscan recognition memory for sentences also suggests that sedation impaired encoding of sentences into memory, with left inferior frontal and temporal lobe responses during light sedation predicting subsequent recognition memory. These findings suggest a graded degradation of cognitive function in response to sedation such that “higher-level” semantic and mnemonic processes can be impaired at relatively low levels of sedation, whereas perceptual processing of speech remains resilient even during deep sedation. These results have important implications for understanding the relationship between speech comprehension and awareness in the healthy brain in patients receiving sedation and in patients with disorders of consciousness.

Closed-loop control of anesthesia using Bispectral index: performance assessment in patients undergoing major orthopedic surgery under combined general and regional anesthesia.

Background The Bispectral Index (BIS) is an electroencephalogram-derived measure of anesthetic depth. A closed-loop anesthesia system was built using BIS as the control variable, a proportional–integral–differential control algorithm, and a propofol target-controlled infusion system as the control actuator. Closed-loop performance was assessed in 10 adult patients. Methods Ten adult patients scheduled to undergo elective hip or knee surgery were enrolled. An epidural cannula was inserted, and 0.5% bupivacaine was used to provide anesthesia to T8 before general anesthesia was induced using the propofol target-controlled infusion system under manual control. After the start of surgery, when anesthesia was clinically adequate, automatic control of anesthesia was commenced using the BIS as the control variable. Adequacy of anesthesia during closed-loop control was assessed clinically and by calculating the median performance error, the median absolute performance error, and the mean offset of the control variable. Results The median performance error and the median absolute performance error were 2.2 and 8.0%, respectively. Mean offset of the BIS from the set point was 0.9. Cardiovascular parameters were stable during closed-loop control. Operating conditions were adequate in all patients but one, who began moving after 45 min of stable anesthesia. No patients reported awareness or recall of intraoperative events. In three patients, there was oscillation of the measured BIS around the set point. Conclusions The system was able to provide clinically adequate anesthesia in 9 of 10 patients. Further studies are required to determine whether control performance can be improved by alterations to the gain factors or by using an effect site–targeted, target-controlled infusion propofol system.

Pharmacokinetic models for propofol—defining and illuminating the devil in the detail

The recently introduced open-target-controlled infusion (TCI) systems can be programmed with any pharmacokinetic model, and allow either plasma- or effect-site targeting. With effect-site targeting the goal is to achieve a user-defined target effect-site concentration as rapidly as possible, by manipulating the plasma concentration around the target. Currently systems are pre-programmed with the Marsh and Schnider pharmacokinetic models for propofol. The former is an adapted version of the Gepts model, in which the rate constants are fixed, whereas compartment volumes and clearances are weight proportional. The Schnider model was developed during combined pharmacokinetic-pharmacodynamic modelling studies. It has fixed values for V1, V3, k(13), and k(31), adjusts V2, k(12), and k(21) for age, and adjusts k(10) according to total weight, lean body mass (LBM), and height. In plasma targeting mode, the small, fixed V1 results in very small initial doses on starting the system or on increasing the target concentration in comparison with the Marsh model. The Schnider model should thus always be used in effect-site targeting mode, in which larger initial doses are administered, albeit still smaller than for the Marsh model. Users of the Schnider model should be aware that in the morbidly obese the LBM equation can generate paradoxical values resulting in excessive increases in maintenance infusion rates. Finally, the two currently available open TCI systems implement different methods of effect-site targeting for the Schnider model, and in a small subset of patients the induction doses generated by the two methods can differ significantly.

Anaesthetic neurotoxicity and neuroplasticity: an expert group report and statement based on the BJA Salzburg Seminar

Although previously considered entirely reversible, general anaesthesia is now being viewed as a potentially significant risk to cognitive performance at both extremes of age. A large body of preclinical as well as some retrospective clinical evidence suggest that exposure to general anaesthesia could be detrimental to cognitive development in young subjects, and might also contribute to accelerated cognitive decline in the elderly. A group of experts in anaesthetic neuropharmacology and neurotoxicity convened in Salzburg, Austria for the BJA Salzburg Seminar on Anaesthetic Neurotoxicity and Neuroplasticity. This focused workshop was sponsored by the British Journal of Anaesthesia to review and critically assess currently available evidence from animal and human studies, and to consider the direction of future research. It was concluded that mounting evidence from preclinical studies reveals general anaesthetics to be powerful modulators of neuronal development and function, which could contribute to detrimental behavioural outcomes. However, definitive clinical data remain elusive. Since general anaesthesia often cannot be avoided regardless of patient age, it is important to understand the complex mechanisms and effects involved in anaesthesia-induced neurotoxicity, and to develop strategies for avoiding or limiting potential brain injury through evidence-based approaches.

A review of postoperative cognitive dysfunction and neuroinflammation associated with cardiac surgery and anaesthesia

Postoperative cognitive dysfunction is receiving increasing attention, particularly as it mainly affects the (growing) elderly population. Until recently, cognitive deficits after cardiac surgery were thought to be caused by physiological disturbances associated with the cardiopulmonary bypass technique. Although the technique of ‘off‐pump’ coronary revascularisation may potentially be associated with improved outcome, long‐term follow‐up studies have failed to demonstrate a significant reduction in the incidence of postoperative cognitive dysfunction. The focus of research is thus shifting from cardiopulmonary bypass to other factors common to both techniques, such as surgery, anaesthesia and patient‐related predisposing factors. Priming of the immune system by ageing and atherosclerosis may result in an exaggerated systemic and cerebral inflammatory response to cardiac surgery and anaesthesia, causing neuronal loss or dysfunction resulting in cognitive dysfunction. We briefly discuss the evidence for cardiopulmonary bypass‐related neuronal injuries in adult cardiac surgery patients, and review the evidence that immune priming is a key factor in the pathogenesis of cognitive dysfunction after cardiac surgery.

Changes in Resting Neural Connectivity during Propofol Sedation

Background The default mode network consists of a set of functionally connected brain regions (posterior cingulate, medial prefrontal cortex and bilateral parietal cortex) maximally active in functional imaging studies under “no task” conditions. It has been argued that the posterior cingulate is important in consciousness/awareness, but previous investigations of resting interactions between the posterior cingulate cortex and other brain regions during sedation and anesthesia have produced inconsistent results. Methodology/Principal Findings We examined the connectivity of the posterior cingulate at different levels of consciousness. “No task” fMRI (BOLD) data were collected from healthy volunteers while awake and at low and moderate levels of sedation, induced by the anesthetic agent propofol. Our data show that connectivity of the posterior cingulate changes during sedation to include areas that are not traditionally considered to be part of the default mode network, such as the motor/somatosensory cortices, the anterior thalamic nuclei, and the reticular activating system. Conclusions/Significance This neuroanatomical signature resembles that of non-REM sleep, and may be evidence for a system that reduces its discriminable states and switches into more stereotypic patterns of firing under sedation.

Postoperative cognitive dysfunction: Involvement of neuroinflammation and neuronal functioning.

Postoperative cognitive dysfunction (POCD) has been hypothesized to be mediated by surgery-induced inflammatory processes, which may influence neuronal functioning either directly or through modulation of intraneuronal pathways, such as the brain derived neurotrophic factor (BDNF) mediated pathway. To study the time course of post-surgical (neuro)inflammation, changes in the BDNF-pathway and POCD, we subjected 3months old male Wistar rats to abdominal surgery and implanted a jugular vein catheter for timed blood sampling. Cognition, affective behavior and markers for (neuro)inflammation, BDNF and neurogenesis were assessed at 1, 2 and 3weeks following surgery. Rats displayed changes in exploratory activity shortly after surgery, associated with postoperatively elevated IL-6 plasma levels. Spatial learning and memory were temporarily impaired in the first 2weeks following surgery, whereas non-spatial cognitive functions seemed unaffected. Analysis of brain tissue revealed increased neuroinflammation (IL-1B and microgliosis) 7days following surgery, decreased BDNF levels on postoperative day 14 and 21, and decreased neurogenesis until at least 21days following surgery. These findings indicate that in young adult rats only spatial learning and memory is affected by surgery, suggesting hippocampal dependent cognition is especially vulnerable to surgery-induced impairment. The observed differences in time course following surgery and relation to plasma IL-6 suggest cognitive dysfunction and mood changes comprise distinct features of postoperative behavioral impairment. The postoperative changes in neuroinflammation, BDNF and neurogenesis may represent aspects of the underlying mechanism for POCD. Future research should be aimed to elucidate how these players interact.

Performance evaluation of two published closed-loop control systems using bispectral index monitoring: a simulation study.

BackgroundAlthough automated closed-loop control systems may improve quality of care, their safety must be proved under extreme control conditions. This study describes a simulation methodology to test automated controllers and its application in a comparison of two published controllers for Bispectral Index (BIS)–guided propofol administration. MethodsA patient simulator was developed to compare controllers. Using input scripts to dictate patient characteristics, target BIS values, and the time course of surgical events, the simulator continuously monitors the infusion pump under control and generates BIS values as a composite of modeled response to drug, perceived stimulation, and random noise. The simulator formats the output stream of BIS data as input to the controller under test to emulate the serial output of the actual BIS monitor. A published model-based controller and a classic proportional integral derivative controller were compared when using the BIS value as a controlled variable. Each controller was tested using a set of 10 virtual patients undergoing a fixed surgical profile that was repeated with BIS targets set at 30, 50, and 70. Controller performance was assessed using median (absolute) prediction error, divergence, wobble, and percentage time within BIS target range metrics. ResultsThe median prediction error was significantly smaller for the proportional integral derivative controller than for the model-based controller. The median absolute prediction error was smaller for the model-based controller than for the proportional integral derivative controller for each BIS target, reaching statistical significance for targets 30 and 50. ConclusionsWhen simulating closed-loop control of BIS using propofol, the use of a patient-individualized, model-based adaptive closed-loop system with effect site control resulted in better control of BIS compared with a standard proportional integral derivative controller with plasma site control. Even under extreme conditions, the modeled-based controller exhibited no behavioral problems.