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1.  Early childhood general anaesthesia exposure and neurocognitive development 
BJA: British Journal of Anaesthesia  2010;105(Suppl 1):i61-i68.
A great deal of concern has recently arisen regarding the safety of anaesthesia in infants and children. There is mounting and convincing preclinical evidence in rodents and non-human primates that anaesthetics in common clinical use are neurotoxic to the developing brain in vitro and cause long-term neurobehavioural abnormalities in vivo. An estimated 6 million children (including 1.5 million infants) undergo surgery and anaesthesia each year in the USA alone, so the clinical relevance of anaesthetic neurotoxicity is an urgent matter of public health. Clinical studies that have been conducted on the long-term neurodevelopmental effects of anaesthetic agents in infants and children are retrospective analyses of existing data. Two large-scale clinical studies are currently underway to further address this issue. The PANDA study is a large-scale, multisite, ambi-directional sibling-matched cohort study in the USA. The aim of this study is to examine the neurodevelopmental effects of exposure to general anaesthesia during inguinal hernia surgery before 36 months of age. Another large-scale study is the GAS study, which will compare the neurodevelopmental outcome between two anaesthetic techniques, general sevoflurane anaesthesia and regional anaesthesia, in infants undergoing inguinal hernia repair. These study results should contribute significant information related to anaesthetic neurotoxicity in children.
PMCID: PMC3000523  PMID: 21148656
anaesthesia, paediatric; children; neurocognitive outcome; neurotoxicity; risk
2.  General anaesthesia does not contribute to long-term post-operative cognitive dysfunction in adults: A meta-analysis 
Indian Journal of Anaesthesia  2011;55(4):358-363.
The contribution of anaesthesia itself to post-operative cognitive dysfunction (POCD) or the potential protective effect of one specific type of anaesthesia on the occurrence of POCD is unclear.
This is a meta-analysis evaluating the effects of the anaesthetic technique (regional vs. general anaesthesia) on POCD of patients undergoing non-cardiac surgery.
Settings and Design:
Meta-analysis performed in a University affiliated hospital.
A search for randomized controlled trials (RCT) comparing regional anaesthesia to general anaesthesia for surgery was done in PUBMED, MEDLINE, EMBASE, EBM Reviews-Cochrane Central Register of Controlled Trials, PsychINFO and Current Contents/all editions in 2009.
Statistical Analysis:
Data were analyzed with comprehensive Meta-analysis Version 2.2.044.
Twenty-six RCTs including 2365 patients: 1169 for regional anaesthesia and 1196 for general anaesthesia were retained. The standardized difference in means for the tests included in the 26 RCTs was -0.08 (95% confidence interval: –0.17–0.01; P value 0.094; I-squared = 0.00%). The assessor was blinded to the anaesthetic technique for 12 of the RCTs including only 798 patients: 393 for regional anaesthesia and 405 for general anaesthesia. The standardized difference in means for these 12 studies is 0.05 (–0.10–0.20; P=0.51; I-squared = 0.00%).
The present meta-analysis does not support the concerns that a single exposure to general anaesthesia in an adult would significantly contribute to permanent POCD after non-cardiac surgery.
PMCID: PMC3190509  PMID: 22013251
Meta-analysis; post-operative cognitive dysfunction; regional anaesthesia
3.  Anaesthesia and physiological monitoring during in vivo imaging of laboratory rodents: considerations on experimental outcomes and animal welfare 
EJNMMI Research  2012;2:44.
The implementation of imaging technologies has dramatically increased the efficiency of preclinical studies, enabling a powerful, non-invasive and clinically translatable way for monitoring disease progression in real time and testing new therapies. The ability to image live animals is one of the most important advantages of these technologies. However, this also represents an important challenge as, in contrast to human studies, imaging of animals generally requires anaesthesia to restrain the animals and their gross motion. Anaesthetic agents have a profound effect on the physiology of the animal and may thereby confound the image data acquired. It is therefore necessary to select the appropriate anaesthetic regime and to implement suitable systems for monitoring anaesthetised animals during image acquisition. In addition, repeated anaesthesia required for longitudinal studies, the exposure of ionising radiations and the use of contrast agents and/or imaging biomarkers may also have consequences on the physiology of the animal and its response to anaesthesia, which need to be considered while monitoring the animals during imaging studies. We will review the anaesthesia protocols and monitoring systems commonly used during imaging of laboratory rodents. A variety of imaging modalities are used for imaging rodents, including magnetic resonance imaging, computed tomography, positron emission tomography, single photon emission computed tomography, high frequency ultrasound and optical imaging techniques such as bioluminescence and fluorescence imaging. While all these modalities are implemented for non-invasive in vivo imaging, there are certain differences in terms of animal handling and preparation, how the monitoring systems are implemented and, importantly, how the imaging procedures themselves can affect mammalian physiology. The most important and critical adverse effects of anaesthetic agents are depression of respiration, cardiovascular system disruption and thermoregulation. When anaesthetising rodents, one must carefully consider if these adverse effects occur at the therapeutic dose required for anaesthesia, if they are likely to affect the image acquisitions and, importantly, if they compromise the well-being of the animals. We will review how these challenges can be successfully addressed through an appropriate understanding of anaesthetic protocols and the implementation of adequate physiological monitoring systems.
PMCID: PMC3467189  PMID: 22877315
Preclinical imaging; Anaesthesia; Physiological monitoring
4.  Optimised Anaesthesia to Reduce Post Operative Cognitive Decline (POCD) in Older Patients Undergoing Elective Surgery, a Randomised Controlled Trial 
PLoS ONE  2012;7(6):e37410.
The study determined the one year incidence of post operative cognitive decline (POCD) and evaluated the effectiveness of an intra-operative anaesthetic intervention in reducing post-operative cognitive impairment in older adults (over 60 years of age) undergoing elective orthopaedic or abdominal surgery.
Methods and Trial Design
The design was a prospective cohort study with a nested randomised, controlled intervention trial, using intra-operative BiSpectral index and cerebral oxygen saturation monitoring to enable optimisation of anaesthesia depth and cerebral oxygen saturation in older adults undergoing surgery.
In the 52 week prospective cohort study (192 surgical patients and 138 controls), mild (χ2 = 17.9 p<0.0001), moderate (χ2 = 7.8 p = 0.005) and severe (χ2 = 5.1 p = 0.02) POCD were all significantly higher after 52 weeks in the surgical patients than among the age matched controls. In the nested RCT, 81 patients were randomized, 73 contributing to the data analysis (34 intervention, 39 control). In the intervention group mild POCD was significantly reduced at 1, 12 and 52 weeks (Fisher’s Exact Test p = 0.018, χ2 = 5.1 p = 0.02 and χ2 = 5.9 p = 0.015), and moderate POCD was reduced at 1 and 52 weeks (χ2 = 4.4 p = 0·037 and χ2 = 5.4 p = 0.02). In addition there was significant improvement in reaction time at all time-points (Vigilance Reaction Time MWU Z =  −2.1 p = 0.03, MWU Z = −2.7 p = 0.004, MWU Z = −3.0 p = 0.005), in MMSE at one and 52 weeks (MWU Z = −2.9 p = 0.003, MWU Z = −3.3 p = 0.001), and in executive function at 12 and 52 weeks (Trail Making MWU Z = −2.4 p = .0.018, MWU Z = −2.4 p = 0.019).
POCD is common and persistent in older adults following surgery. The results of the nested RCT indicate the potential benefits of intra-operative monitoring of anaesthetic depth and cerebral oxygenation as a pragmatic intervention to reduce post-operative cognitive impairment.
Trial Registration ISRCTN39503939
PMCID: PMC3376123  PMID: 22719840
5.  Local anaesthesia for pain control during outpatient hysteroscopy: systematic review and meta-analysis 
Objective To compare the effects of different types of local anaesthetic for pain control during outpatient hysteroscopy.
Design Systematic review and meta-analysis of randomised controlled trials.
Setting Outpatient hysteroscopy clinics.
Participants Women undergoing diagnostic or operative hysteroscopy as outpatients—that is, without general anaesthesia.
Study selection criteria Medline, Embase, CINAHL, the Cochrane library, and reference lists of relevant studies. Two reviewers independently selected trials. Data were abstracted on quality, characteristics, and results.
Results There were 20 trials (2851 participants). Data from 15 of these were meta-analysed in subgroups defined by type of intervention and study quality. Intracervical (standardised mean difference −0.36, 95% confidence interval −0.61 to −0.10, I2=0%) and paracervical (−1.28, −2.22 to −0.35, I2=97%) injections of local anaesthetic significantly reduced the pain in women undergoing hysteroscopy as outpatients, whereas transcervical (−0.11, −0.31 to 0.10, I2=27%) and topical application (−0.32, −0.97 to 0.33, I2= 90%) did not. Meta-regression showed that paracervical injection was superior to the other anaesthetic methods (P=0.04), a finding that was supported by the high quality subgroup of studies. Use of local anaesthetic did not have a significant effect on the incidence of vasovagal episodes (P=0.09).
Conclusions Paracervical local anaesthetic injection is the best method of pain control for women undergoing hysteroscopy as outpatients.
PMCID: PMC2844502  PMID: 20332307
6.  Anaesthetics-Induced Neurotoxicity in Developing Brain: An Update on Preclinical Evidence 
Brain Sciences  2014;4(1):136-149.
Every year millions of young people are treated with anaesthetic agents for surgery and sedation in a seemingly safe manner. However, growing and convincing preclinical evidence in rodents and nonhuman primates, together with recent epidemiological observations, suggest that exposure to anaesthetics in common clinical use can be neurotoxic to the developing brain and lead to long-term neurological sequelae. These findings have seriously questioned the safe use of general anaesthetics in obstetric and paediatric patients. The mechanisms and human applicability of anaesthetic neurotoxicity and neuroprotection have remained under intense investigation over the past decade. Ongoing pre-clinical investigation may have significant impact on clinical practice in the near future. This review represents recent developments in this rapidly emerging field. The aim is to summarise recently available laboratory data, especially those being published after 2010, in the field of anaesthetics-induced neurotoxicity and its impact on cognitive function. In addition, we will discuss recent findings in mechanisms of early-life anaesthetics-induced neurotoxicity, the role of human stem cell-derived models in detecting such toxicity, and new potential alleviating strategies.
PMCID: PMC4066242  PMID: 24961704
anaesthetics; neuroapoptosis; neurotoxicity; neonates; developing brain
7.  Differential Effects of Anaesthesia on the phMRI Response to Acute Ketamine Challenge 
Pharmacological-challenge magnetic resonance imaging (phMRI) is powerful new tool enabling researchers to map the central effects of neuroactive drugs in vivo. To employ this technique pre-clinically, head movements and the stress of restraint are usually reduced by maintaining animals under general anaesthesia. However, interactions between the drug of interest and the anaesthetic employed may potentially confound data interpretation. NMDA receptor (NMDAR) antagonists used widely to mimic schizophrenia have recently been shown to interact with the anaesthetic halothane. It may be the case that neural and cerebrovascular responses to NMDAR antagonists are dependent on the types of anaesthetic used.
We compared the phMRI response to NMDAR antagonist ketamine in rats maintained under α-chloralose to those under isoflurane anaesthesia. A randomized placebo/vehicle controlled design was used in each of the anaesthetic groups.
Changes in the anaesthetic agent resulted in two very different profiles of activity. In the case of α-chloralose, positive activations in cortical and sub-cortical structures reflected a response which was similar to patterns seen in healthy human volunteers and metabolic maps of conscious rats. However, the use of isoflurane completely reversed such effects, causing widespread deactivations in the cortex and hippocampus.
This study provides initial evidence for a drug-anesthetic interaction between ketamine and isoflurane that is very different from responses to α-chloralose-ketamine.
PMCID: PMC3378209  PMID: 22737655
Anaesthesia; anesthesia; NMDA; ketamine; schizophrenia; α-chloralose; isoflurane; phMRI; fMRI; BOLD; rat
8.  Does regional compared to local anaesthesia influence outcome after arteriovenous fistula creation? 
Trials  2013;14:263.
An arteriovenous fistula is the optimal form of vascular access in patients with end-stage renal failure requiring haemodialysis. Unfortunately, approximately one-third of fistulae fail at an early stage. Different anaesthetic techniques can influence factors associated with fistula success, such as intraoperative blood flow and venous diameter. A regional anaesthetic brachial plexus block results in vasodilatation and improved short- and long-term fistula flow compared to the infiltration of local anaesthetic alone. This, however, has not yet been shown in a large trial to influence long-term fistula patency, the ultimate clinical measure of success.
The aim of this study is to compare whether a regional anaesthetic block, compared to local anaesthetic infiltration, can improve long-term fistula patency.
This study is an observer-blinded, randomised controlled trial. Patients scheduled to undergo creation of either brachial or radial arteriovenous fistulae will receive a study information sheet, and consent will be obtained in keeping with the Declaration of Helsinki. Patients will be randomised to receive either: (i) an ultrasound guided brachial plexus block using lignocaine with adrenaline and levobupivicaine, or (ii) local anaesthetic infiltration with lignocaine and levobupivicaine.
A total of 126 patients will be recruited. The primary outcome is fistula primary patency at three months. Secondary outcomes include primary patency at 1 and 12 months, secondary patency and fistula flow at 1, 3 and 12 months, flow on first haemodialysis, procedural pain, patient satisfaction, change in cephalic vein diameter pre- and post-anaesthetic, change in radial or brachial artery flow pre- and post-anaesthetic, alteration of the surgical plan after anaesthesia as guided by vascular mapping with ultrasound, and fistula infection requiring antibiotics.
No large randomised controlled trial has examined the influence of brachial plexus block compared with local anaesthetic infiltration on the long-term patency of arteriovenous fistulae. If the performance of brachial plexus block increases fistulae patency, this will have significant clinical and financial benefits as the number of patients able to commence haemodialysis when planned should increase, and the number of “redo” or revision procedures should be reduced.
Trial registration
This study has been approved by the West of Scotland Research Ethics Committee 5 (reference no. 12/WS/0199) and is registered with the database (reference no. NCT01706354).
PMCID: PMC3765116  PMID: 23958289
Fistula; Patency; Flow; Anaesthetic; Local; Nerve block; Renal failure
9.  Peak and averaged bicoherence for different EEG patterns during general anaesthesia 
Changes in nonlinear neuronal mechanisms of EEG generation in the course of general anaesthesia have been extensively investigated in research literature. A number of EEG signal properties capable of tracking these changes have been reported and employed in anaesthetic depth monitors. The degree of phase coupling between different spectral components is a marker of nonlinear EEG generators and is claimed to be an important aspect of BIS. While bicoherence is the most direct measure of phase coupling, according to published research it is not directly used in the calculation of BIS, and only limited studies of its association with anaesthetic depth and level of consciousness have been published. This paper investigates bicoherence parameters across equal band and unequal band bifrequency regions, during different states of anaesthetic depth relating to routine clinical anaesthesia, as determined by visual inspection of EEG.
41 subjects scheduled for day surgery under general anaesthesia were recruited into this study. EEG bicoherence was analysed using average and smoothed-peak estimates calculated over different regions on the bifrequency plane. Statistical analysis of associations between anaesthetic depth/state of consciousness and bicoherence estimates included linear regression using generalised linear mixed effects models (GLMs), ROC curves and prediction probability (Pk).
Bicoherence estimates for the δ_θ region on the bifrequency plane were more sensitive to anaesthetic depth changes compared to other bifrequency regions. Smoothed-peak bicoherence displayed stronger associations than average bicoherence. Excluding burst suppression and large transients, the δ_θ peak bicoherence was significantly associated with level of anaesthetic depth (z = 25.74, p < 0.001 and R2 = 0.191). Estimates of Pk for this parameter were 0.889(0.867-0.911) and 0.709(0.689-0.729) respectively for conscious states and anaesthetic depth levels (comparable BIS estimates were 0.928(0.905-0.950) and 0.801(0.786-0.816)). Estimates of linear regression and areas under ROC curves supported Pk findings. Bicoherence for eye movement artifacts were the most distinctive with respect to other EEG patterns (average |z| value 13.233).
This study quantified associations between deepening anaesthesia and increase in bicoherence for different frequency components and bicoherence estimates. Increase in bicoherence was also established for eye movement artifacts. While identified associations extend earlier findings of bicoherence changes with increases in anaesthetic drug concentration, results indicate that the unequal band bifrequency region, δ_θ, provides better predictive capabilities than equal band bifrequency regions.
PMCID: PMC2998515  PMID: 21092128
10.  The Effects of Local Anaesthetics on QT Parameters during Thoracic Epidural Anaesthesia Combined with General Anaesthesia: Ropivacaine versus Bupivacaine 
Balkan medical journal  2013;30(4):410-414.
Many studies focusing on the effects of local anaesthetics on QT intervals have been performed, but the articles evaluating the relationship between thoracic epidural anaesthesia combined with general anaesthesia and QT parameters are very limited.
We aimed to compare the effects of bupivacaine and ropivacaine on QT interval, corrected QT, dispersion of QT, and corrected dispersion of QT in patients undergoing lung resection under thoracic epidural anaesthesia combined with general anaesthesia.
Study Design:
Prospective clinical study.
Thirty ASA physical status 1–3 patients requiring thoracic epidural anaesthesia combined with general anaesthesia for thoracic surgery. Patients were randomly assigned to two groups, which were allocated to receive either bupivacaine (Group B) or ropivacaine (Group R) during thoracic epidural anaesthesia. Following haemodynamic monitoring, a thoracic epidural catheter was inserted. Local anaesthetic at an average dose of 1.5 mL/ segment was given through an epidural catheter. The same general anaesthesia protocol was administered in both groups. Records and measurements were performed on 10 phases that were between the thoracic epidural catheter insertion to the 5th min of endobronchial intubation. In all phases, systolic arterial pressure, diastolic arterial pressure, mean arterial pressure, heart rate, peripheral O2 saturation, and electrocardiogram monitoring were performed in patients. All QT parameters were recorded by 12-lead electrocardiogram and analysed manually by a cardiologist.
QT intervals were similar between two groups. In Group R, corrected QT values at the 20th min of local anaesthetic injection and the 5th min of endobronchial intubation were shorter than those in Group B (p<0.05). The basal dispersion of QT and dispersion of QT values at the 1st min of propofol injection were shorter than those in Group R (p<0.05). The corrected dispersion of QT value at the 1st min of propofol injection was shorter in Group R (p<0.05). In Group R, the decrease in mean arterial pressure at the 1st min of fentanyl injection was significant compared with Group B (p<0.05). There was no significant difference between the groups with respect to heart rate and complications.
The corrected QT, dispersion of QT, and corrected dispersion of QT intervals were slightly longer in the patients receiving bupivacaine compared with those receiving ropivacaine in various phases of the present study.
PMCID: PMC4115939  PMID: 25207150
Bupivacaine; ropivacaine; QT parameters; thoracic epidural anaesthesia; local anaesthetics
11.  Voluntary reporting system in anaesthesia: is there a link between undesirable and critical events? 
Quality in Health Care : QHC  2000;9(4):203-209.
P Garnerin, quality manager and F Clergue, department head and professor
J-F Sicard, anaesthetist and F Bonnet, department head and professor
Background—Reporting systems in anaesthesia have generally focused on critical events (including death) to trigger investigations of latent and active errors. The decrease in the rate of these critical events calls for a broader definition of significant anaesthetic events, such as hypotension and bradycardia, to monitor anaesthetic care. The association between merely undesirable events and critical events has not been established and needs to be investigated by voluntary reporting systems.
Objectives—To establish whether undesirable anaesthetic events are correlated with critical events in anaesthetic voluntary reporting systems.
Methods—As part of a quality improvement project, a systematic reporting system was implemented for monitoring 32 events during elective surgery in our hospital in 1996. The events were classified according to severity (critical/undesirable) and nature (process/outcome) and control charts and logistic regression were used to analyse the data.
Results—During a period of 30 months 22% of the 6439 procedures were associated with anaesthetic events, 15% of which were critical and 31% process related. A strong association was found between critical outcome events and critical process events (OR 11.5 (95% confidence interval (CI) 4.4 to 27.8)), undesirable outcome events (OR 4.8 (95% CI 2.0 to 11.8)), and undesirable process events (OR 4.8 (95% CI 1.3 to 13.4)). For other classes of events, risk factors were related to the course of anaesthesia (duration, occurrence of other events) and included factors determined during the pre-anaesthetic visit (risk of haemorrhage, difficult intubation or allergic reaction).
Conclusion—Undesirable events are associated with more severe events and with pre-anaesthetic risk factors. The way in which information on significant events can be used is discussed, including better use of preoperative information, reduction in the collection of redundant information, and more structured reporting.
(Quality in Health Care 2000;9:203–209)
Key Words: reporting system; correlation analysis; quality assessment; adverse events; anaesthesia
PMCID: PMC1743544  PMID: 11101704
12.  Use of brachial plexus blockade and medetomidine-ketamine-isoflurane anaesthesia for repair of radio-ulna fracture in an adult cheetah (acinonyx jubatus) 
BMC Veterinary Research  2014;10(1):249.
Regional anaesthetic techniques have been used in combination with systemic analgesics during small animal surgery to provide multimodal analgesia. Brachial plexus nerves block using local anaesthetics provides analgesia of the thoracic limb through desensitization of the nerves that provide sensory and motor innervation. This has been shown to reduce intra-operative anesthetic requirements and provide postoperative pain relief. Decreasing the doses of general anaesthetics allows more stable cardiopulmonary function during anaesthesia and the development of less side effects. The present case reports a successful use of brachial plexus blockade to supplement medetomidine-ketamine-isoflurane anaesthesia for repair of radio-ulna fracture in an adult cheetah (acinonyx jubatus).
Case presentation
An adult male Cheetah weighing about 65 kg was presented with a history of leg carrying lameness of the left forelimb sustained following a car accident a week earlier. Clinical examination under general anaesthesia revealed slight dehydration and a swelling with a wound on the caudo-medial aspect of the left radio-ulna region. Crepitation was present on manipulation and radiography confirmed a complete transverse radio-ulna fracture of the left forelimb, which required open reduction and internal fixation. Brachial plexus blockade using lignocaine hydrochloride was used to supplement medetomidine-ketamine-isoflurane anaesthesia for the surgical procedure. Isoflurane anaesthesia was maintained at 0.5 - 2.0% throughout the surgical procedure, which was uneventful. Temperature and cardio-pulmonary parameters remained stable intra-operatively. Limb paralysis extended for 5 hours post-operatively, suggesting prolonged anaesthesia.
To the researchers’ knowledge, this is the first reported case of the use of brachial plexus blockade to supplement general anaesthesia to facilitate forelimb surgery in an adult cheetah. The use of brachial plexus block with a light plane of general anaesthesia proved to be successful. Brachial plexus block had a sparing effect on isoflurane anaesthesia as evidenced by the concentration used for maintenance of anaesthesia and the stability of the cardiopulmonary function. Moreover, absence of autonomic cardiopulmonary reactions to the surgical manipulation may be attributed to the efficacy of brachial plexus block. This anaesthesia protocol is therefore recommended for surgeries of the forelimb in wild cats.
PMCID: PMC4200215  PMID: 25301165
Wild cats; Forelimb fracture; Anaesthesia protocol
13.  Multimodal system designed to reduce errors in recording and administration of drugs in anaesthesia: prospective randomised clinical evaluation 
Objective To clinically evaluate a new patented multimodal system (SAFERSleep) designed to reduce errors in the recording and administration of drugs in anaesthesia.
Design Prospective randomised open label clinical trial.
Setting Five designated operating theatres in a major tertiary referral hospital.
Participants Eighty nine consenting anaesthetists managing 1075 cases in which there were 10 764 drug administrations.
Intervention Use of the new system (which includes customised drug trays and purpose designed drug trolley drawers to promote a well organised anaesthetic workspace and aseptic technique; pre-filled syringes for commonly used anaesthetic drugs; large legible colour coded drug labels; a barcode reader linked to a computer, speakers, and touch screen to provide automatic auditory and visual verification of selected drugs immediately before each administration; automatic compilation of an anaesthetic record; an on-screen and audible warning if an antibiotic has not been administered within 15 minutes of the start of anaesthesia; and certain procedural rules—notably, scanning the label before each drug administration) versus conventional practice in drug administration with a manually compiled anaesthetic record.
Main outcome measures Primary: composite of errors in the recording and administration of intravenous drugs detected by direct observation and by detailed reconciliation of the contents of used drug vials against recorded administrations; and lapses in responding to an intermittent visual stimulus (vigilance latency task). Secondary: outcomes in patients; analyses of anaesthetists’ tasks and assessments of workload; evaluation of the legibility of anaesthetic records; evaluation of compliance with the procedural rules of the new system; and questionnaire based ratings of the respective systems by participants.
Results The overall mean rate of drug errors per 100 administrations was 9.1 (95% confidence interval 6.9 to 11.4) with the new system (one in 11 administrations) and 11.6 (9.3 to 13.9) with conventional methods (one in nine administrations) (P=0.045 for difference). Most were recording errors, and, though fewer drug administration errors occurred with the new system, the comparison with conventional methods did not reach significance. Rates of errors in drug administration were lower when anaesthetists consistently applied two key principles of the new system (scanning the drug barcode before administering each drug and keeping the voice prompt active) than when they did not: mean 6.0 (3.1 to 8.8) errors per 100 administrations v 9.7 (8.4 to 11.1) respectively (P=0.004). Lapses in the vigilance latency task occurred in 12% (58/471) of cases with the new system and 9% (40/473) with conventional methods (P=0.052). The records generated by the new system were more legible, and anaesthetists preferred the new system, particularly in relation to long, complex, and emergency cases. There were no differences between new and conventional systems in respect of outcomes in patients or anaesthetists’ workload.
Conclusions The new system was associated with a reduction in errors in the recording and administration of drugs in anaesthesia, attributable mainly to a reduction in recording errors. Automatic compilation of the anaesthetic record increased legibility but also increased lapses in a vigilance latency task and decreased time spent watching monitors.
Trial registration Australian New Zealand Clinical Trials Registry No 12608000068369.
PMCID: PMC3178276  PMID: 21940742
14.  Percutaneous regional compared with local anaesthesia for facial lacerations: a randomised controlled trial 
Objective: Facial lacerations are usually repaired after local infiltration of an anaesthetic agent. Regional nerve blocks of the face offer several theoretical advantages over local infiltration. This study compared the pain of injection and anaesthetic efficacy of percutaneous regional and local anaesthesia for facial lacerations.
Study design: Randomised clinical trial.
Participants: Convenience sample of emergency department patients with facial lacerations requiring suturing in anatomical areas innervated by a regional nerve (supraorbital, infraorbital, or mental).
Interventions: Facial lacerations treated using standard wound care. Lacerations were randomised to local or regional infiltration of lidocaine (lignocaine) 1% with adrenaline (epinephrine) 1:100 000 using a number 27 needle.
Outcomes: Pain of injection on 100 mm visual analogue scale (VAS) and need for rescue anaesthetic infiltration before suturing.
Data analysis: Group comparisons were with Student's t test and χ2 test. This study had 80% power to detect a 20 mm difference in pain of injection (two tailed, α = 0.05).
Results: 36 patients were randomised to local (18) and regional (18) anaesthesia. Mean (SD) age was 20 (14); 19% were female. Groups were similar in baseline characteristics. Patients in the regional anaesthesia group experienced more pain during infiltration than patients in the local anaesthesia group (42.4 mm v 24.8 mm, mean difference 17.6 mm (95% CI 0.3 to 35.6 mm) and were more likely to require additional infiltration of a local anaesthetic (28% v 0%, (95% CI 6% to 50%)) than patients in the local anaesthetic group.
Conclusions: Local infiltration of anaesthetics for facial lacerations is less painful and results in more effective anaesthesia than percutaneous regional infiltration.
PMCID: PMC1726525  PMID: 15611540
15.  Closed loop anaesthesia at high altitude (3505 m above sea level): Performance characteristics of an indigenously developed closed loop anaesthesia delivery system 
Indian Journal of Anaesthesia  2012;56(3):238-242.
Closed loop anaesthesia delivery systems (CLADSs) are a recent advancement in accurate titration of anaesthetic drugs. They have been shown to be superior in maintaining adequate depth of anaesthesia with few fluctuations as compared with target-controlled infusion or manual titration of drug delivery.
Twenty patients scheduled to undergo general abdominal or orthopaedic procedures under general anaesthesia at Leh (3505 m above sea level) were recruited as subjects. Anaesthesia was delivered by a patented closed loop system that uses the Bispectral Index (BIS™) as a feedback parameter to titrate the rate of propofol infusion. All vital parameters, drug infusion rate and the BIS™ values were continuously recorded and stored online by the system. The data generated was analysed for the adequacy of anaesthetic depth, haemodynamic stability and post-operative recovery parameters.
The CLADS was able to maintain a BIS™ within ±10 of the target of 50 for 85.0±7.8% of the time. Haemodynamics were appropriately maintained (heart rate and mean arterial blood pressure were within 25% of baseline values for 91.2±2.2% and 94.1±3% of the total anaesthesia time, respectively). Subjects were awake within a median of 3 min from cessation of drug infusion and achieved fitness to recovery room discharge within a median of 15 min. There were no adverse events or report of awareness under anaesthesia.
The study demonstrates the safety of our CLADS at high altitude. It seeks to extend the use of our system in challenging anaesthesia environments. The system performance was also adequate and no adverse events were recorded.
PMCID: PMC3425282  PMID: 22923821
Bispectral index; closed loop anaesthesia; high altitude; propofol
16.  Improving access to preparatory information for children undergoing general anaesthesia for tooth extraction and their families: study protocol for a Phase III randomized controlled trial 
Trials  2014;15:219.
Children can find anaesthesia induction especially distressing and postoperative psychological and physical morbidity are common. Preparation programmes for general anaesthesia (GA) are highly effective in reducing this distress. A Phase II study has already verified the effectiveness of a prototype preoperative GA-coping computer game to help children cope with induction in a dental GA setting. The biggest patient users of pediatric GA services in the UK are children who need to have teeth removed (estimated to be 100,000 yearly). Tooth decay is the most common disease in children worldwide. This study is a Phase III randomized controlled trial (RCT) and will evaluate the effectiveness of the new internet version of this game.
The Phase III RCT will use a double-blind three-armed design. The clinical trial will recruit up to 210 children and will compare the web-based game against standard care and another non-medical game. At least 53 patients in each group will be required for 90% statistical power. Distress will be assessed through an evaluation of the child’s behaviour during the visit and later parental reports of physical and psychological morbidity. The satisfaction of parents and children will be measured; the mode of usage of the web-based game will be automatically recorded and the impact on the service (for example, recovery time and throughput) will be reported.
The Phase III study primary outcome will measure: (1) patient experience: acceptance of anaesthetic induction, child cooperation and distress, reduction of peri- and postoperative morbidity, child and family satisfaction, and (2) service improvement: anaesthetic time and improvement in throughput. Measures will be administered at baseline, at the time of the GA treatment visit, and at 48 hours and one week postoperatively.
This study aims to determine the effectiveness of an online GA-coping game for children and families undergoing tooth extraction under GA.
Trial registration
ISRCTN18265148 (registered 24 November 2013).
PMCID: PMC4229849  PMID: 24919430
General anaesthesia; Children; Preparatory information; Coping; Cognitive behavioural therapy; Role modelling; Early childhood caries; Dental anxiety; Randomized controlled trial (RCT)
17.  Anaesthetic mechanisms: update on the challenge of unravelling the mystery of anaesthesia 
European journal of anaesthesiology  2009;26(10):807-820.
General anaesthesia is administered each day to thousands of patients worldwide. Although more than 160 years have passed since the first successful public demonstration of anaesthesia, a detailed understanding of the anaesthetic mechanism of action of these drugs is still lacking. An important early observation was the Meyer-Overton correlation, which associated the potency of an anaesthetic with its lipid solubility. This work focuses attention on the lipid membrane as a likely location for anaesthetic action. With the advent of cellular electrophysiology and molecular biology techniques, tools to dissect the components of the lipid membrane have led, in recent years, to the widespread acceptance of proteins, namely receptors and ion channels, as more likely targets for the anaesthetic effect. Yet these accumulated data have not produced a comprehensive explanation for how these drugs produce CNS depression. In this review, we follow the story of anaesthesia mechanisms research from its historical roots to the intensely neurophysiologic inquiries regarding it today. We will also describe recent findings that identify specific neuroanatomical locations mediating the actions of some anaesthetic agents.
PMCID: PMC2778226  PMID: 19494779
anaesthetic mechanisms; anaesthetic targets; anaesthetics; ion channels; receptors
18.  Impact of anaesthetics and surgery on neurodevelopment: an update 
BJA: British Journal of Anaesthesia  2013;110(Suppl 1):i53-i72.
Accumulating preclinical and clinical evidence suggests the possibility of neurotoxicity from neonatal exposure to general anaesthetics. Here, we review the weight of the evidence from both human and animal studies and discuss the putative mechanisms of injury and options for protective strategies. Our review identified 55 rodent studies, seven primate studies, and nine clinical studies of interest. While the preclinical data consistently demonstrate robust apoptosis in the nervous system after anaesthetic exposure, only a few studies have performed cognitive follow-up. Nonetheless, the emerging evidence that the primate brain is vulnerable to anaesthetic-induced apoptosis is of concern. The impact of surgery on anaesthetic-induced brain injury has not been adequately addressed yet. The clinical data, comprising largely retrospective cohort database analyses, are inconclusive, in part due to confounding variables inherent in these observational epidemiological approaches. This places even greater emphasis on prospective approaches to this problem, such as the ongoing GAS trial and PANDA study.
PMCID: PMC3667344  PMID: 23542078
brain, anaesthesia, molecular effects; nerve, damage (postoperative); nerve, neurotransmitters; nerve, regeneration
19.  Airway reactions and emergence times in general laryngeal mask airway anaesthesia 
Desflurane's short emergence time supports fast track anaesthesia. Data on the rate of upper airway complications and emergence time when desflurane is used with laryngeal mask airway (LMA) are controversial and limited.
To compare recovery time variables and the rates of upper airway adverse events in patients with an LMA undergoing general surgery with desflurane, sevoflurane, isoflurane or propofol anaesthesia.
A systematic review and meta-analysis of randomised controlled trials (RCTs).
A systematic search for eligible RCTs in Embase (Elsevier) and in PubMed (National Library of Medicine) databases up to September 2013.
RCTs investigating the rates of cough overall, cough at emergence, laryngospasm, time to eye opening, time to removal of the LMA, time to respond to command and time to state date of birth in patients with an LMA, during emergence from desflurane, sevoflurane, isoflurane or propofol anaesthesia.
Thirteen RCTs were included and analysed. We found a strong interstudy variability. There was no difference in the rates of upper airway events between desflurane and sevoflurane or between desflurane and a control group consisting of all the other anaesthetics combined. Comparing desflurane (n = 284) with all other anaesthetic groups (n = 313), the risk ratio [95% confidence interval (95% CI)] was 1.12 (0.63 to 2.02, P = 0.70). Cough at emergence was only measured in patients receiving desflurane (n = 148) and sevoflurane (n = 146): the risk ratio (95% CI) was 1.49 (0.55 to 4.02, P = 0.43). Laryngospasm was rare and there was no significant difference in its incidence when desflurane (n = 262) was compared with all other anaesthetics combined (n = 289; risk ratio 1.03; 95% CI 0.33 to 3.20, P = 0.96). The times of all emergence variables were significantly faster in the desflurane group than in all other groups.
When using an LMA, upper airway adverse reactions in association with desflurane anaesthesia were no different from those noted with sevoflurane, isoflurane or propofol anaesthesia. Emergence from general anaesthesia with desflurane is significantly faster than all the other anaesthetics. Due to interstudy variations and the small size of the trials, further large-scale, multicentre studies are required to confirm or refute the results of this meta-analysis.
PMCID: PMC4276573  PMID: 25545286
20.  GALA: an international multicentre randomised trial comparing general anaesthesia versus local anaesthesia for carotid surgery 
Trials  2008;9:28.
Patients who have severe narrowing at or near the origin of the internal carotid artery as a result of atherosclerosis have a high risk of ischaemic stroke ipsilateral to the arterial lesion. Previous trials have shown that carotid endarterectomy improves long-term outcomes, particularly when performed soon after a prior transient ischaemic attack or mild ischaemic stroke. However, complications may occur during or soon after surgery, the most serious of which is stroke, which can be fatal. It has been suggested that performing the operation under local anaesthesia, rather than general anaesthesia, may be safer. Therefore, a prospective, randomised trial of local versus general anaesthesia for carotid endarterectomy was proposed to determine whether type of anaesthesia influences peri-operative morbidity and mortality, quality of life and longer term outcome in terms of stroke-free survival.
A two-arm, parallel group, multicentre randomised controlled trial with a recruitment target of 5000 patients. For entry into the study, in the opinion of the responsible clinician, the patient requiring an endarterectomy must be suitable for either local or general anaesthesia, and have no clear indication for either type. All patients with symptomatic or asymptomatic internal carotid stenosis for whom open surgery is advised are eligible. There is no upper age limit. Exclusion criteria are: no informed consent; definite preference for local or general anaesthetic by the clinician or patient; patient unlikely to be able to co-operate with awake testing during local anaesthesia; patient requiring simultaneous bilateral carotid endarterectomy; carotid endarterectomy combined with another operation such as coronary bypass surgery; and, the patient has been randomised into the trial previously. Patients are randomised to local or general anaesthesia by the central trial office. The primary outcome is the proportion of patients alive, stroke free (including retinal infarction) and without myocardial infarction 30 days post-surgery. Secondary outcomes include the proportion of patients alive and stroke free at one year; health related quality of life at 30 days; surgical adverse events, re-operation and re-admission rates; the relative cost of the two methods of anaesthesia; length of stay and intensive and high dependency bed occupancy.
Trial registration
Current Controlled Trials ISRCTN00525237
PMCID: PMC2413207  PMID: 18495004
21.  Anaesthetic neurotoxicity and neuroplasticity: an expert group report and statement based on the BJA Salzburg Seminar 
BJA: British Journal of Anaesthesia  2013;111(2):143-151.
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.
PMCID: PMC3711392  PMID: 23722106
anaesthesia, general; anaesthetics; cognitive disorder; neurotoxicity syndromes; postoperative complications
22.  Early postoperative cognitive dysfunction and postoperative delirium after anaesthesia with various hypnotics: study protocol for a randomised controlled trial - The PINOCCHIO trial 
Trials  2011;12:170.
Postoperative delirium can result in increased postoperative morbidity and mortality, major demand for postoperative care and higher hospital costs. Hypnotics serve to induce and maintain anaesthesia and to abolish patients' consciousness. Their persisting clinical action can delay postoperative cognitive recovery and favour postoperative delirium. Some evidence suggests that these unwanted effects vary according to each hypnotic's specific pharmacodynamic and pharmacokinetic characteristics and its interaction with the individual patient.
We designed this study to evaluate postoperative delirium rate after general anaesthesia with various hypnotics in patients undergoing surgical procedures other than cardiac or brain surgery. We also aimed to test whether delayed postoperative cognitive recovery increases the risk of postoperative delirium.
After local ethics committee approval, enrolled patients will be randomly assigned to one of three treatment groups. In all patients anaesthesia will be induced with propofol and fentanyl, and maintained with the anaesthetics desflurane, or sevoflurane, or propofol and the analgesic opioid fentanyl.
The onset of postoperative delirium will be monitored with the Nursing Delirium Scale every three hours up to 72 hours post anaesthesia. Cognitive function will be evaluated with two cognitive test batteries (the Short Memory Orientation Memory Concentration Test and the Rancho Los Amigos Scale) preoperatively, at baseline, and postoperatively at 20, 40 and 60 min after extubation.
Statistical analysis will investigate differences in the hypnotics used to maintain anaesthesia and the odds ratios for postoperative delirium, the relation of early postoperative cognitive recovery and postoperative delirium rate. A subgroup analysis will be used to categorize patients according to demographic variables relevant to the risk of postoperative delirium (age, sex, body weight) and to the preoperative score index for delirium.
The results of this comparative anaesthesiological trial should whether each the three hypnotics tested is related to a significantly different postoperative delirium rate. This information could ultimately allow us to select the most appropriate hypnotic to maintain anaesthesia for specific subgroups of patients and especially for those at high risk of postoperative delirium.
Registered at Number NCT00507195
PMCID: PMC3155116  PMID: 21733178
23.  Recovery index, attentiveness and state of memory after xenon or isoflurane anaesthesia: a randomized controlled trial 
BMC Anesthesiology  2010;10:5.
Performance of patients immediately after anaesthesia is an area of special interest and so a clinical trial was conducted to compare Xenon with Isoflurane anaesthesia. In order to assess the early cognitive recovery the syndrome short test (SST) according to Erzigkeit (Geromed GmbH) was applied.
ASA I and II patients undergoing long and short surgical interventions were randomised to receive either general anaesthesia with Xenon or Isoflurane. The primary endpoint was the validated SST which covering memory disturbances and attentiveness. The test was used on the day prior to intervention, one and three hours post extubation. The secondary endpoint was the recovery index (RI) measured after the end of the inhalation of Xenon or Isoflurane. In addition the Aldrete score was evaluated up to 180 min. On the first post-operative day the patients rated the quality of the anaesthetic using a scoring system from 1-6.
The demographics of the groups were similar. The sum score of the SST delivered a clear trend one hour post extubation and a statistically significant superiority for Xenon three hours post extubation (p < 0.01). The RI likewise revealed a statistically significant superiority of Xenon 5 minutes post extubation (p < 0.01). The Aldrete score was significantly higher for 45 min. The scoring system results were also better after Xenon anaesthesia (p < 0.001).
The results show that recovery from anaesthesia and the early return of post-operative cognitive functions are significantly better after Xenon anaesthesia compared to Isoflurane. The results of the RI for Xenon are similar with the previously published results.
Trial Registration
The trial was registered with the number ISRCTN01110844
PMCID: PMC2877044  PMID: 20459661
24.  Local anaesthetics and regional anaesthesia for preventing chronic pain after surgery 
Regional anaesthesia may reduce the rate of persistent (chronic) pain after surgery, a frequent and debilitating condition.
To compare local anaesthetics and regional anaesthesia versus conventional analgesia for the prevention of persistent pain six or 12 months after surgery.
Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 4), PubMed (1966 to April 2012), EMBASE (1966 to May 2012) and CINAHL (1966 to May 2012) without any language restriction. We used a combination of free text search and controlled vocabulary search. The results were limited to randomized controlled clinical trials (RCTs). We conducted a handsearch in reference lists of included trials, review articles and conference abstracts.
Selection criteria
We included RCTs comparing local anaesthetics or regional anaesthesia versus conventional analgesia with a pain outcome at six or 12 months after surgery.
Data collection and analysis
Two authors independently assessed trial quality and extracted data, including information on adverse events. We contacted study authors for additional information. Results are presented as pooled odds ratios (OR) with 95% confidence intervals (CI), based on random-effects models (inverse variance method). We grouped studies according to surgical interventions. We employed the Chi2 test and calculated the I2 statistic to investigate study heterogeneity.
Main results
We identified 23 RCTs studying local anaesthetics or regional anaesthesia for the prevention of persistent (chronic) pain after surgery. Data from a total of 1090 patients with outcomes at six months and of 441 patients with outcomes at 12 months were presented. No study included children. We pooled data from 250 participants after thoracotomy, with outcomes at six months. Data favoured regional anaesthesia for the prevention of chronic pain at six months after thoracotomy with an OR of 0.33 (95% CI 0.20 to 0.56). We pooled two studies on paravertebral block for breast cancer surgery; the pooled data of 89 participants with outcomes at five to six months favoured paravertebral block with an OR of 0.37 (95% CI 0.14 to 0.94).The methodological quality of the included studies was intermediate. Adverse effects were not studied systematically and were reported sparsely. Clinical heterogeneity, attrition and sparse outcome data hampered the assessment of effects, especially at 12 months.
Authors’ conclusions
Epidural anaesthesia may reduce the risk of developing chronic pain after thoracotomy in about one patient out of every four patients treated. Paravertebral block may reduce the risk of chronic pain after breast cancer surgery in about one out of every five women treated. Our conclusions are significantly weakened by performance bias, shortcomings in allocation concealment, considerable attrition and incomplete outcome data. We caution that our evidence synthesis is based on only a few, small studies. More studies with high methodological quality, addressing various types of surgery and different age groups, including children, are needed.
PMCID: PMC4004344  PMID: 23076930
25.  A prospective trial of local versus general anaesthesia for arthroscopic surgery of the knee. 
We set out to determine if arthroscopic knee surgery was acceptable to patients and their surgeon when carried out using a local anaesthetic infiltration technique. Patients awaiting arthroscopy were randomly allocated to have either a local or a general anaesthetic. The same surgeon (NPT) carried out all the procedures. The demographic profile was similar in the two groups, as were the diagnosis and the surgical procedures. The only difference between the two groups was that those performed under local anaesthesia did not have a limb tourniquet inflated. The time spent in the theatre suite was similar in each group. This did not include the recovery time in the general anaesthetic group. The duration of the operation was longer in the local anaesthetic group (P = 0.05). A simple 0 to 10 scoring system indicated that patients preferred a local anaesthetic but the surgeon preferred to have the patient asleep (P > 0.05). Those having a local anaesthetic required less physiotherapy (P = 0.025) and more of them returned to work and sport earlier (P = 0.05). We attributed this to not having sustained pressure-induced tissue damage to the thigh muscle as they did not have a tourniquet inflated. We had a 4% failure rate in the local anaesthetic group. Arthroscopic surgery is already a well-established day case procedure and our findings have a financial implication (a saving of 25 pounds per case) as well as identifying a safer technique in the medically unfit. Unfortunately, this technique is not suitable for the investigation and treatment of all knee problems. There are certain constraints, viz the very anxious patient, acute problems, children, larger arthroscopic procedures and the inability to perform an examination under anaesthetic but, overall, it is a useful and effective way of performing a common surgical procedure.
PMCID: PMC2503043  PMID: 9326126

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