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1.  Impact of anaesthetics and surgery on neurodevelopment: an update 
BJA: British Journal of Anaesthesia  2013;110(Suppl 1):i53-i72.
Summary
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.
doi:10.1093/bja/aet054
PMCID: PMC3667344  PMID: 23542078
brain, anaesthesia, molecular effects; nerve, damage (postoperative); nerve, neurotransmitters; nerve, regeneration
2.  Isoflurane and sevoflurane increase interleukin-6 levels through the nuclear factor-kappa B pathway in neuroglioma cells 
BJA: British Journal of Anaesthesia  2013;110(Suppl 1):i82-i91.
Background
Isoflurane can increase pro-inflammatory cytokine interleukin (IL)-6 levels. However, the up-stream mechanism remains unknown. Nuclear factor-kappa B (NF-κB) promotes the generation of pro-inflammatory cytokines. We examined the effects of isoflurane and sevoflurane on the NF-κB signalling pathway and its association with IL-6 levels in cultured cells.
Methods
H4 human neuroglioma cells (H4 cells), and mouse primary neurones and microglia were treated with 2% isoflurane or 4.1% sevoflurane for 6 h, for analysis of IL-6 and NF-κB. Pyrrolidine dithiocarbamate (an NF-κB inhibitor) or 2-deoxy-d-glucose (2-DG) (an inhibitor of glucose glycolysis) was applied 1 h before anaesthetic treatment.
Results
Isoflurane or sevoflurane treatment increased the levels of IL-6 [isoflurane: 410% (54); sevoflurane: 290% (24)], the nuclear levels of NF-κB [isoflurane: 170% (36); sevoflurane: 320% (30)], and the transcription activity of NF-κB in H4 cells. Moreover, isoflurane enhanced the transcription activity of NF-κB in mouse microglia, but not primary neurones. Finally, pyrrolidine dithiocarbamate and 2-DG attenuated isoflurane-induced increases in IL-6 and NF-κB, and the transcription activity of NF-κB.
Conclusions
These studies in H4 cells suggest that the NF-κB signalling pathway could contribute to isoflurane or sevoflurane-induced neuroinflammation. This could lead to the targeted intervention of anaesthetic-induced neuroinflammation.
doi:10.1093/bja/aet115
PMCID: PMC3667345  PMID: 23604542
anaesthetic; interleukin-6; NF-κB
3.  Isoflurane affects the cytoskeleton but not survival, proliferation, or synaptogenic properties of rat astrocytes in vitro 
BJA: British Journal of Anaesthesia  2013;110(Suppl 1):i19-i28.
Background
More than half of the cells in the brain are glia and yet the impact of general anaesthetics on these cells is largely unexamined. We hypothesized that astroglia, which are strongly implicated in neuronal well-being and synapse formation and function, are vulnerable to adverse effects of isoflurane.
Methods
Cultured rat astrocytes were treated with 1.4% isoflurane in air or air alone for 4 h. Viability, proliferation, and cytoskeleton were assessed by colorimetric assay, immunocytochemistry, or a migration assay at the end of treatment or 2 days later. Also, primary rat cortical neurones were treated for 4 days with conditioned medium from control [astrocyte-conditioned media (ACM)], or isoflurane-exposed astrocytes (Iso-ACM) and synaptic puncta were assessed by synapsin 1 and PSD-95 immunostaining.
Results
By several measures, isoflurane did not kill astrocytes. Nor, based on incorporation of a thymidine analogue, did it inhibit proliferation. Isoflurane had no effect on F-actin but reduced expression of α-tubulin and glial fibrillary acidic protein both during exposure (P<0.05 and P<0.001, respectively) and 2 days later (P<0.01), but did not impair astrocyte motility. ACM increased formation of PSD-95 but not synapsin 1 positive puncta in neuronal cultures, and Iso-ACM was equally effective.
Conclusions
Isoflurane decreased expression of microtubule and intermediate filament proteins in astrocytes in vitro, but did not affect their viability, proliferation, motility, and ability to support synapses.
doi:10.1093/bja/aet169
PMCID: PMC3667346  PMID: 23722058
astrocytes; isoflurane
4.  Propofol-induced apoptosis of neurones and oligodendrocytes in fetal and neonatal rhesus macaque brain 
BJA: British Journal of Anaesthesia  2013;110(Suppl 1):i29-i38.
Background
Exposure of the fetal or neonatal non-human primate (NHP) brain to isoflurane or ketamine for 5 h causes widespread apoptotic degeneration of neurones, and exposure to isoflurane also causes apoptotic degeneration of oligodendrocytes (OLs). The present study explored the apoptogenic potential of propofol in the fetal and neonatal NHP brain.
Method
Fetal rhesus macaques at gestational age 120 days were exposed in utero, or postnatal day 6 rhesus neonates were exposed directly for 5 h to propofol anaesthesia (n=4 fetuses; and n=4 neonates) or to no anaesthesia (n=4 fetuses; n=5 neonates), and the brains were systematically evaluated 3 h later for evidence of apoptotic degeneration of neurones or glia.
Results
Exposure of fetal or neonatal NHP brain to propofol caused a significant increase in apoptosis of neurones, and of OLs at a stage when OLs were just beginning to myelinate axons. Apoptotic degeneration affected similar brain regions but to a lesser extent than we previously described after isoflurane. The number of OLs affected by propofol was approximately equal to the number of neurones affected at both developmental ages. In the fetus, neuroapoptosis affected particularly subcortical and caudal regions, while in the neonate injury involved neocortical regions in a distinct laminar pattern and caudal brain regions were less affected.
Conclusions
Propofol anaesthesia for 5 h caused death of neurones and OLs in both the fetal and neonatal NHP brain. OLs become vulnerable to the apoptogenic action of propofol when they are beginning to achieve myelination competence.
doi:10.1093/bja/aet173
PMCID: PMC3667347  PMID: 23722059
anaesthetics i.v., propofol; developing brain; neurones; non-human primates; oligodendroglia; toxicity
5.  Distinct long-term neurocognitive outcomes after equipotent sevoflurane or isoflurane anaesthesia in immature rats 
BJA: British Journal of Anaesthesia  2013;110(Suppl 1):i39-i46.
Background
Many anaesthetics when given to young animals cause cell death and learning deficits that persist until much later in life. Recent attempts to compare the relative safety or toxicity between different agents have not adequately controlled for the relative dose of anaesthetic given, thereby making direct comparisons difficult.
Methods
Isoflurane or sevoflurane were given at 1 minimum alveolar concentration (MAC) for 4 h to postnatal day 7 (P7) rat pups. Beginning at P75 these animals underwent fear conditioning and at P83 Morris water maze testing to assess working memory, short-term memory and early long-term memory using delays of 1 min, 1 h, and 4 h.
Results
No difference between groups was seen in fear conditioning experiments. Morris water maze learning was equivalent between groups, and no difference was seen in working memory. Sevoflurane-treated animals had a deficit in early long-term memory, and isoflurane-treated animals had a deficit in both short-term and early long-term memory.
Conclusions
Both isoflurane and sevoflurane delivered at 1 MAC for 4 h to immature rats caused a deficit in long-term memory. Isoflurane also caused a deficit in short-term memory. Isoflurane might be more detrimental than sevoflurane in very young animals.
doi:10.1093/bja/aet103
PMCID: PMC3695640  PMID: 23592692
animals; isoflurane toxicity; memory drug effects; newborn; sevoflurane toxicity
6.  Potentiation of GABAA receptor activity by volatile anaesthetics is reduced by α5GABAA receptor-preferring inverse agonists 
BJA: British Journal of Anaesthesia  2013;110(Suppl 1):i73-i81.
Background
Animal studies have shown that memory deficits in the early post-anaesthetic period can be prevented by pre-treatment with an inverse agonist that preferentially inhibits α5 subunit-containing γ-aminobutyric acid type A (α5GABAA) receptors. The goal of this in vitro study was to determine whether inverse agonists that inhibit α5GABAA receptors reduce anaesthetic potentiation of GABAA receptor activity.
Methods
Cultures of hippocampal neurones were prepared from Swiss white mice, wild-type mice (genetic background C57BL/6J and Sv129Ev) and α5GABAA receptor null mutant (Gabra5−/−) mice. Whole-cell voltage clamp techniques were used to study the effects of the α5GABAA receptor-preferring inverse agonists L-655,708 and MRK-016 on anaesthetic potentiation of GABA-evoked currents.
Results
L-655,708 (50 nM) reduced sevoflurane potentiation of GABA-evoked current in wild-type neurones but not Gabra5−/− neurones, and produced a rightward shift in the sevoflurane concentration–response plot [sevoflurane EC50: 1.9 (0.1) mM; sevoflurane+L-655,708 EC50: 2.4 (0.2) mM, P<0.05]. Similarly, L-655,708 (50 nM) reduced isoflurane potentiation of GABA-evoked current [isoflurane: 4.0 (0.6) pA pF−1; isoflurane+L-655,708: 3.1 (0.5) pA pF−1, P<0.01]. MRK-016 also reduced sevoflurane and isoflurane enhancement of GABA-evoked current [sevoflurane: 1.5 (0.1) pA pF−1; sevoflurane+MRK-016 (10 nM): 1.2 (0.1) pA pF−1, P<0.05; isoflurane: 3.5 (0.3) pA pF−1; isoflurane+MRK-016 (1 nM): 2.9 (0.2) pA pF−1, P<0.05].
Conclusions
L-655,708 and MRK-016 reduced the potentiation by inhaled anaesthetics of GABAA receptor activated by a low concentration of GABA. Future studies are required to determine whether this effect contributes to the memory preserving properties of inverse agonists after anaesthesia.
doi:10.1093/bja/aet038
PMCID: PMC3732063  PMID: 23535829
anaesthetics volatile, sevoflurane, isoflurane; brain, GABA; electrophysiology
7.  Mitochondrial protectant pramipexole prevents sex-specific long-term cognitive impairment from early anaesthesia exposure in rats  
BJA: British Journal of Anaesthesia  2013;110(Suppl 1):i47-i52.
Background
Exposure to general anaesthesia during critical stages of brain development results in long-lasting cognitive impairment. Co-administration of protective agents could minimize the detrimental effects of anaesthesia. Co-administration of R(+)pramipexole (PPX), a synthetic aminobenzothiazol derivative that restores mitochondrial integrity, prevents anaesthesia-induced mitochondrial and neuronal damage and prevents early development of cognitive impairment. Here, we determine the protective effects of PPX into late adulthood in male and female rats.
Methods
Postnatal day 7 rats of both sexes were exposed to mock anaesthesia or combined midazolam, nitrous oxide, and isoflurane anaesthesia for 6 h with or without PPX. Cognitive abilities were assessed between 5 and 7 months of age using Morris water maze spatial navigation tasks.
Results
Examination of spatial reference memory revealed that female, but not male, neonatal rats exposed to anaesthesia showed slowing of acquisition rates, which was significantly improved with PPX treatment. Examination of memory retention revealed that both male and female anaesthesia-treated rats have impaired memory retention performance compared with sham controls. Co-treatment with PPX resulted in improvement in memory retention in both sexes.
Conclusion
PPX provides long-lasting protection against cognitive impairment known to occur when very young animals are exposed to anaesthesia during the peak of brain development. Anaesthesia-induced cognitive impairment appears to be sex-specific with females being more vulnerable than males, suggesting that they could benefit more from early prevention.
doi:10.1093/bja/aet073
PMCID: PMC3732064  PMID: 23616588
anaesthetics volatile, isoflurane; anaesthetics gases, nitrous oxide; memory; neonates; oxygen, toxicity; recovery, cognitive
8.  Reply from the authors 
BJA: British Journal of Anaesthesia  2014;112(6):1121-1123.
doi:10.1093/bja/aeu173
PMCID: PMC4020385  PMID: 24829427
9.  Inflammatory response, immunosuppression, and cancer recurrence after perioperative blood transfusions 
BJA: British Journal of Anaesthesia  2013;110(5):690-701.
Summary
Debate on appropriate triggers for transfusion of allogeneic blood products and their effects on short- and long-term survival in surgical and critically ill patients continue with no definitive evidence or decisive resolution. Although transfusion-related immune modulation (TRIM) is well established, its influence on immune competence in the recipient and its effects on cancer recurrence after a curative resection remains controversial. An association between perioperative transfusion of allogeneic blood products and risk for recurrence has been shown in colorectal cancer in randomized trials; whether the same is true for other types of cancer remains to be determined. This article focuses on the laboratory, animal, and clinical evidence to date on the mechanistic understanding of inflammatory and immune-modulatory effects of blood products and their significance for recurrence in the cancer surgical patient.
doi:10.1093/bja/aet068
PMCID: PMC3630286  PMID: 23599512
cancer; transfusion 
10.  Population pharmacokinetics of epsilon-aminocaproic acid in infants undergoing craniofacial reconstruction surgery 
BJA: British Journal of Anaesthesia  2013;110(5):788-799.
Background
Understanding the clinical pharmacology of the antifibrinolytic epsilon-aminocaproic acid (EACA) is necessary for rational drug administration in children. The aim of this study is to determine the pharmacokinetics (PKs) of EACA in infants aged 6–24 months undergoing craniofacial reconstruction surgery.
Methods
Cohorts of six infants were enrolled sequentially to one of the three escalating loading dose–continuous i.v. infusion (CIVI) regimens: 25 mg kg−1, 10 mg kg−1 h−1; 50 mg kg−1, 20 mg kg−1 h−1; 100 mg kg−1, 40 mg kg−1 h−1. Plasma EACA concentrations were determined using a validated high-performance liquid chromatography-tandem mass spectrometry assay. A population non-linear mixed effects modelling approach was used to characterize EACA PKs.
Results
Population PK parameters of EACA were estimated using a two-compartment disposition model with weight expressed as an allometric covariate and an age effect. The typical patient in this study had an age of 38.71 weeks and a weight of 8.82 kg. PK parameters for this typical patient were: pre-/postoperative plasma drug clearance of 32 ml min−1 (3.6 ml kg−1 min−1), inter-compartmental clearance of 42.4 ml min−1 (4.8 ml min−1 kg−1), central volume of distribution of 1.27 litre (0.14 litre kg−1), and peripheral volume of distribution of 2.53 litre (0.29 litre kg−1). Intra-operative clearance and central volume of distribution were 89% and 80% of the pre-/postoperative value, respectively.
Conclusions
EACA clearance increased with weight and age. The dependence of clearance on body weight supports weight-based dosing. Based on this study, a loading dose of 100 mg kg−1 followed by a CIVI of 40 mg kg−1 h−1 is appropriate to maintain target plasma EACA concentrations in children aged 6–24 months undergoing these procedures.
doi:10.1093/bja/aes507
PMCID: PMC3695654  PMID: 23353035
aminocaproic acid; antifibrinolytic agents; craniofacial abnormalities; infants; paediatrics; pharmacology
11.  Presynaptic inhibition of the release of multiple major central nervous system neurotransmitter types by the inhaled anaesthetic isoflurane 
BJA: British Journal of Anaesthesia  2012;110(4):592-599.
Background
Presynaptic effects of general anaesthetics are not well characterized. We tested the hypothesis that isoflurane exhibits transmitter-specific effects on neurotransmitter release from neurochemically and functionally distinct isolated mammalian nerve terminals.
Methods
Nerve terminals from adult male rat brain were prelabelled with [3H]glutamate and [14C]GABA (cerebral cortex), [3H]norepinephrine (hippocampus), [14C]dopamine (striatum), or [3H]choline (precursor of [3H]acetylcholine; striatum). Release evoked by depolarizing pulses of 4-aminopyridine (4AP) or elevated KCl was quantified using a closed superfusion system.
Results
Isoflurane at clinical concentrations (<0.7 mM; ∼2 times median anaesthetic concentration) inhibited Na+ channel-dependent 4AP-evoked release of the five neurotransmitters tested in a concentration-dependent manner. Isoflurane was a more potent inhibitor [expressed as IC50 (sem)] of glutamate release [0.37 (0.03) mM; P<0.05] compared with the release of GABA [0.52 (0.03) mM], norepinephrine [0.48 (0.03) mM], dopamine [0.48 (0.03) mM], or acetylcholine [0.49 (0.02) mM]. Inhibition of Na+ channel-independent release evoked by elevated K+ was not significant at clinical concentrations of isoflurane, with the exception of dopamine release [IC50=0.59 (0.03) mM].
Conclusions
Isoflurane inhibited the release of the major central nervous system neurotransmitters with selectivity for glutamate release, consistent with both widespread inhibition and nerve terminal-specific presynaptic effects. Glutamate release was most sensitive to inhibition compared with GABA, acetylcholine, dopamine, and norepinephrine release due to presynaptic specializations in ion channel expression, regulation, and/or coupling to exocytosis. Reductions in neurotransmitter release by volatile anaesthetics could contribute to altered synaptic transmission, leading to therapeutic and toxic effects involving all major neurotransmitter systems.
doi:10.1093/bja/aes448
PMCID: PMC3600942  PMID: 23213036
acetylcholine; γ-aminobutyric acid; anaesthetics; dopamine; exocytosis; glutamate; Na+ channels; nerve terminal; neurotransmitter release; norepinephrine
12.  Falls and major orthopaedic surgery with peripheral nerve blockade: a systematic review and meta-analysis 
BJA: British Journal of Anaesthesia  2013;110(4):518-528.
Summary
The objective of this systematic review with meta-analysis was to determine the risk for falls after major orthopaedic surgery with peripheral nerve blockade. Electronic databases from inception through January 2012 were searched. Eligible studies evaluated falls after peripheral nerve blockade in adult patients undergoing major lower extremity orthopaedic surgery. Independent reviewers working in duplicate extracted study characteristics, validity, and outcomes data. The Peto odds ratio (OR) with 95% confidence intervals (CIs) were estimated from each study that compared continuous lumbar plexus blockade with non-continuous blockade or no blockade using a fixed effects model. Ten studies (4014 patients) evaluated the number of falls as an outcome. Five studies did not contain comparison groups. The meta-analysis of five studies [four randomized controlled trials (RCTs) and one cohort] compared continuous lumbar plexus blockade (631 patients) with non-continuous blockade or no blockade (964 patients). Fourteen falls occurred in the continuous lumbar plexus block group when compared with five falls within the non-continuous block or no block group (attributable risk 1.7%; number needed to harm 59). Continuous lumbar plexus blockade was associated with a statistically significant increase in the risk for falls [Peto OR 3.85; 95% CI (1.52, 9.72); P=0.005; I2=0%]. Evidence was low (cohort) to high (RCTs) quality. Continuous lumbar plexus blockade in adult patients undergoing major lower extremity orthopaedic surgery increases the risk for postoperative falls compared with non-continuous blockade or no blockade. However, attributable risk was not outside the expected probability of postoperative falls after orthopaedic surgery.
doi:10.1093/bja/aet013
PMCID: PMC3600943  PMID: 23440367
accidental falls; anaesthesia, conduction; arthroplasty, replacement, hip; arthroplasty, replacement, knee; muscle weakness; nerve block
13.  Impact of perioperative dexamethasone on postoperative analgesia and side-effects: systematic review and meta-analysis 
BJA: British Journal of Anaesthesia  2012;110(2):191-200.
Background
The analgesic efficacy and adverse effects of a single perioperative dose of dexamethasone are unclear. We performed a systematic review to evaluate the impact of a single i.v. dose of dexamethasone on postoperative pain and explore adverse events associated with this treatment.
Methods
MEDLINE, EMBASE, CINAHL, and the Cochrane Register were searched for randomized, controlled studies that compared dexamethasone vs placebo or an antiemetic in adult patients undergoing general anaesthesia and reported pain outcomes.
Results
Forty-five studies involving 5796 patients receiving dexamethasone 1.25–20 mg were included. Patients receiving dexamethasone had lower pain scores at 2 h {mean difference (MD) −0.49 [95% confidence interval (CI): −0.83, −0.15]} and 24 h [MD −0.48 (95% CI: −0.62, −0.35)] after surgery. Dexamethasone-treated patients used less opioids at 2 h [MD −0.87 mg morphine equivalents (95% CI: −1.40 to −0.33)] and 24 h [MD −2.33 mg morphine equivalents (95% CI: −4.39, −0.26)], required less rescue analgesia for intolerable pain [relative risk 0.80 (95% CI: 0.69, 0.93)], had longer time to first dose of analgesic [MD 12.06 min (95% CI: 0.80, 23.32)], and shorter stays in the post-anaesthesia care unit [MD −5.32 min (95% CI: −10.49 to −0.15)]. There was no dose–response with regard to the opioid-sparing effect. There was no increase in infection or delayed wound healing with dexamethasone, but blood glucose levels were higher at 24 h [MD 0.39 mmol litre−1 (95% CI: 0.04, 0.74)].
Conclusions
A single i.v. perioperative dose of dexamethasone had small but statistically significant analgesic benefits.
doi:10.1093/bja/aes431
PMCID: PMC3544008  PMID: 23220857
analgesics, opioid; dexamethasone; glucocorticoids; hyperglycaemia; pain, postoperative; surgical wound infection
14.  Perioperative central nervous system injury in neonates 
BJA: British Journal of Anaesthesia  2012;109(Suppl 1):i60-i67.
Summary
Anaesthetic-induced developmental neurotoxicity (AIDN) has been clearly established in laboratory animal models. The possibility of neurotoxicity during uneventful anaesthetic procedures in human neonates or infants has led to serious questions about the safety of paediatric anaesthesia. However, the applicability of animal data to clinical anaesthesia practice remains uncertain. The spectre of cerebral injury due to cerebral hypoperfusion, metabolic derangements, coexisting disease, and surgery itself further muddles the picture. Given the potential magnitude of the public health importance of this issue, the clinician should be cognisant of the literature and ongoing investigations on AIDN, and raise awareness of the risks of both surgery and anaesthesia.
doi:10.1093/bja/aes424
PMCID: PMC3521998  PMID: 23242752
anaesthesia, paediatric; brain injury; paediatric; surgery
15.  Increased electroencephalographic gamma activity reveals awakening from isoflurane anaesthesia in rats 
BJA: British Journal of Anaesthesia  2012;109(5):782-789.
Background
Animal studies often require reliable measures for anaesthetic drug effects. Lately, EEG-based depth of anaesthesia estimation has been widely applied to rat models. This study investigated the reliability of different EEG spectral properties in revealing awakening from isoflurane anaesthesia in rats.
Methods
Adult Wistar rats with previously implanted frontal epidural electrodes were anaesthetized using isoflurane. The anaesthesia was slowly lightened until awakening, as observed by the first spontaneous movement, after which anaesthesia was induced again by increasing the isoflurane concentration. EEG was recorded during the recovery and induction periods, and the spectrograms and 23 quantitative spectral parameters used in the depth of anaesthesia estimation were calculated from the signals.
Results
The awakening was accompanied by a decrease in EEG activity at frequencies below 25 Hz, while the activity at higher frequencies (25–150 Hz) was increased. Whereas the behaviour of parameters used to measure activity in the lower frequencies was subject to variability between animals, the increase in higher frequency activity was more consistent, resulting in a statistically significant change in the relative gamma power parameters at the moment of awakening.
Conclusions
The increase in frontal relative gamma activity, especially in the 50–150 Hz frequency band, seems to be the most reliable EEG indicator for the awakening of a rat from isoflurane anaesthesia. A number of other spectral measures can also be used to detect this event. However, the role of gamma frequencies in the performance of these parameters is crucial.
doi:10.1093/bja/aes265
PMCID: PMC3470445  PMID: 22907339
anaesthesia, depth; anaesthetics volatile, isoflurane; monitoring, depth of anaesthesia; monitoring, electroencephalography; rat
16.  Caveolae and propofol effects on airway smooth muscle 
BJA: British Journal of Anaesthesia  2012;109(3):444-453.
Background
The i.v. anaesthetic propofol produces bronchodilatation. Airway relaxation involves reduced intracellular Ca2+ ([Ca2+]i) in airway smooth muscle (ASM) and lipid rafts (caveolae), and constitutional caveolin proteins regulate [Ca2+]i. We postulated that propofol-induced bronchodilatation involves caveolar disruption.
Methods
Caveolar fractions of human ASM cells were tested for propofol content. [Ca2+]i responses of ASM cells loaded with fura-2 were performed in the presence of 10 µM histamine with and without clinically relevant concentrations of propofol (10 and 30 μM and intralipid control). Effects on sarcoplasmic reticulum (SR) Ca2+ release were evaluated in zero extracellular Ca2+ using the blockers Xestospongin C and ryanodine. Store-operated Ca2+ entry (SOCE) after SR depletion was evaluated using established techniques. The role of caveolin-1 in the effect of propofol was tested using small interference RNA (siRNA) suppression. Changes in intracellular signalling cascades relevant to [Ca2+]i and force regulation were also evaluated.
Results
Propofol was present in ASM caveolar fractions in substantial concentrations. Exposure to 10 or 30 µM propofol form decreased [Ca2+]i peak (but not plateau) responses to histamine by ∼40%, an effect persistent in zero extracellular Ca2+. Propofol effects were absent in caveolin-1 siRNA-transfected cells. Inhibition of ryanodine receptors prevented propofol effects on [Ca2+]i, while propofol blunted [Ca2+]i responses to caffeine. Propofol reduced SOCE, an effect also prevented by caveolin-1 siRNA. Propofol effects were associated with decreased caveolin-1 expression and extracellular signal-regulated kinase phosphorylation.
Conclusions
These novel data suggest a role for caveolae (specifically caveolin-1) in propofol-induced bronchodilatation. Due to its lipid nature, propofol may transiently disrupt caveolar regulation, thus altering ASM [Ca2+]i.
doi:10.1093/bja/aes130
PMCID: PMC3415286  PMID: 22542538
bronchial smooth muscle; bronchodilatation; calcium regulation; caveolin; intravenous anaesthetic; signalling
17.  Risks for impaired cerebral autoregulation during cardiopulmonary bypass and postoperative stroke 
BJA: British Journal of Anaesthesia  2012;109(3):391-398.
Background
Impaired cerebral autoregulation may predispose patients to cerebral hypoperfusion during cardiopulmonary bypass (CPB). The purpose of this study was to identify risk factors for impaired autoregulation during coronary artery bypass graft, valve surgery with CPB, or both and to evaluate whether near-infrared spectroscopy (NIRS) autoregulation monitoring could be used to identify this condition.
Methods
Two hundred and thirty-four patients were monitored with transcranial Doppler and NIRS. A continuous, moving Pearson's correlation coefficient was calculated between mean arterial pressure (MAP) and cerebral blood flow (CBF) velocity, and between MAP and NIRS data, to generate the mean velocity index (Mx) and cerebral oximetry index (COx), respectively. Functional autoregulation is indicated by an Mx and COx that approach zero (no correlation between CBF and MAP); impaired autoregulation is indicated by an Mx and COx approaching 1. Impaired autoregulation was defined as an Mx ≥0.40 at all MAPs during CPB.
Results
Twenty per cent of patients demonstrated impaired autoregulation during CPB. Based on multivariate logistic regression analysis, time-averaged COx during CPB, male gender, , CBF velocity, and preoperative aspirin use were independently associated with impaired CBF autoregulation. Perioperative stroke occurred in six of 47 (12.8%) patients with impaired autoregulation compared with five of 187 (2.7%) patients with preserved autoregulation (P=0.011).
Conclusions
Impaired CBF autoregulation occurs in 20% of patients during CPB. Patients with impaired autoregulation are more likely than those with functional autoregulation to have perioperative stroke. Non-invasive monitoring autoregulation may provide an accurate means to predict impaired autoregulation.
Clinical trials registration. www.clinicaltrials.gov (NCT00769691).
doi:10.1093/bja/aes148
PMCID: PMC3415287  PMID: 22661748
cardiac surgery; cardiopulmonary bypass; cerebral autoregulation; stroke
18.  Single sevoflurane exposure decreases neuronal nitric oxide synthase levels in the hippocampus of developing rats 
BJA: British Journal of Anaesthesia  2012;109(2):225-233.
Background
The use of general anaesthetics in young children and infants has raised concerns regarding the adverse effects of these drugs on brain development. Sevoflurane might have harmful effects on the developing brain; however, these effects have not been well investigated.
Methods
Postnatal day 7 (P7) Sprague–Dawley rats were continuously exposed to 2.3% sevoflurane for 6 h. We used the Fox battery test and Morris water maze (MWM) to examine subsequent neurobehavioural performance. Cleaved caspase-3 and neuronal nitric oxide synthase (nNOS) were quantified by immunoblotting, and the Nissl staining was used to observe the histopathological changes in the hippocampus.
Results
A single 6 h sevoflurane exposure at P7 rats resulted in increased cleaved caspase-3 expression and decreased nNOS levels in the hippocampus, and induced the loss of pyramidal neurones in the CA1 and CA3 subfields of the hippocampus at P7–8. These changes were accompanied by temporal retardation of sensorimotor reflexes. However, neither the Fox battery test at P1–21 nor the MWM test at P28–32 showed differences between the air- and sevoflurane-treated groups.
Conclusions
Although early exposure to sevoflurane increases activated caspase-3 expression and neuronal loss and decreases nNOS in the neonatal hippocampus, it does not affect subsequent neurobehavioural performances in juvenile rats.
doi:10.1093/bja/aes121
PMCID: PMC3393078  PMID: 22535834
anaesthetic, sevoflurane; caspase 3; hippocampus; memory; neuronal nitric oxide synthase; sevoflurane
19.  Electroacupuncture inhibition of hyperalgesia in an inflammatory pain rat model: involvement of distinct spinal serotonin and norepinephrine receptor subtypes 
BJA: British Journal of Anaesthesia  2012;109(2):245-252.
Background
Although acupuncture analgesia is well documented, its mechanisms have not been thoroughly clarified. We previously showed that electroacupuncture (EA) activates supraspinal serotonin- and norepinephrine-containing neurones that project to the spinal cord. This study investigates the involvement of spinal alpha(2)-adrenoceptors (α2-ARs) and 5-hydroxytryptamine (serotonin) receptors (5-HTRs) in EA effects on an inflammatory pain rat model.
Methods
Inflammatory hyperalgesia was induced by injecting complete Freund's adjuvant (CFA, 0.08 ml) into the plantar surface of one hind paw and assessed by paw withdrawal latency (PWL) to a noxious thermal stimulus. The selective α2a-AR antagonist BRL-44408, α2b-AR antagonist imiloxan hydrochloride, 5-HT2B receptor (5-HT2BR) antagonist SB204741, 5-HT3R antagonist LY278584, or 5-HT1AR antagonists NAN-190 hydrobromide, or WAY-100635 were intrathecally administered 20 min before EA or sham EA, which was given 2 h post-CFA at acupoint GB30.
Results
EA significantly increased PWL compared with sham [7.20 (0.46) vs 5.20 (0.43) s]. Pretreatment with α2a-AR [5.35 (0.45) s] or 5-HT1AR [5.22 (0.38) s] antagonists blocked EA-produced anti-hyperalgesia; α2b-AR, 5-HT2BR, and 5-HT3R antagonist pretreatment did not. Sham plus these antagonists did not significantly change PWL compared with sham plus vehicle, indicating that the antagonists had little effect on PWL. Immunohistochemical staining demonstrated that α2a-ARs are on primary afferents and 5-HT1ARs are localized in N-methyl-d-aspartic acid (NMDA) subunit NR1-containing neurones in the spinal dorsal horn.
Conclusions
The data show that α2a-ARs and 5-HT1ARs are involved in the EA inhibition of inflammatory pain and that the NMDA receptors are involved in EA action.
doi:10.1093/bja/aes136
PMCID: PMC3393079  PMID: 22628394
acupuncture; norepinephrine; pain; serotonin; spinal cord
21.  Imaging pain: a potent means for investigating pain mechanisms in patients 
Summary
Chronic pain is a state of physical suffering strongly associated with feelings of anxiety, depression and despair. Disease pathophysiology, psychological state, and social milieu can influence chronic pain, but can be difficult to diagnose based solely on clinical presentation. Here, we review brain neuroimaging research that is shaping our understanding of pain mechanisms, and consider how such knowledge might lead to useful diagnostic tools for the management of persistent pain in individual patients.
doi:10.1093/bja/aet174
PMCID: PMC3690317  PMID: 23794647
chronic pain; neuroimaging, magnetic resonance imaging, functional
22.  Ventilatory responses after major surgery and high dependency care 
BJA: British Journal of Anaesthesia  2012;108(5):864-871.
Background
Disturbed breathing during sleep, with episodic upper airway obstruction, is frequent after major surgery. Ventilatory responses to hypercapnia and hypoxia during episodes of airway obstruction are difficult to investigate because the usual measure, that of ventilation, has been attenuated by the obstruction. We simulated the blood gas stimulus associated with obstruction to allow investigation of the responses.
Methods
To assess ventilatory responses, we studied 19 patients, mean age 59 (19–79), first at discharge from high dependency care after major abdominal surgery and then at surgical review, ∼6 weeks later. Exhaled gas was analysed and inspired gas adjusted to simulate changes that would occur during airway obstruction. Changes in ventilation were measured over the following 45–70 s. Studies were done from air breathing if possible, and also from an increased inspired oxygen concentration.
Results
During simulated obstruction, hypercapnia developed similarly in all the test conditions. Arterial oxygen saturation decreased significantly more rapidly when the test was started from air breathing. The mean ventilatory response was 5.8 litre min−2 starting from air breathing and 4.5 litre min−2 with oxygen breathing. The values 6 weeks later were 5.9 and 4.3 litre min−2, respectively (P=0.05, analysis of variance). There was no statistical difference between the responses starting from air and those on oxygen.
Conclusions
After major surgery, ventilatory responses to hypercapnia and hypoxaemia associated with airway obstruction are small and do not improve after 6 weeks. With air breathing, arterial oxygen desaturation during simulated rebreathing is substantial.
doi:10.1093/bja/aes017
PMCID: PMC3325049  PMID: 22369766
general surgery; pulmonary ventilation; respiratory insufficiency
23.  Impact of phenylephrine administration on cerebral tissue oxygen saturation and blood volume is modulated by carbon dioxide in anaesthetized patients† 
BJA: British Journal of Anaesthesia  2012;108(5):815-822.
Background
Multiple studies have shown that cerebral tissue oxygen saturation () is decreased after phenylephrine treatment. We hypothesized that the negative impact of phenylephrine administration on is affected by arterial blood carbon dioxide partial pressure () because CO2 is a powerful modulator of cerebrovascular tone.
Methods
In 14 anaesthetized healthy patients, i.v. phenylephrine bolus was administered to increase the mean arterial pressure ∼20–30% during hypocapnia, normocapnia, and hypercapnia. and cerebral blood volume (CBV) were measured using frequency domain near-infrared spectroscopy, a quantitative technology. Data collection occurred before and after each treatment.
Results
Phenylephrine caused a significant decrease in during hypocapnia [=−3.4 (1.5)%, P<0.001], normocapnia [=−2.4 (1.5)%, P<0.001], and hypercapnia [=−1.4 (1.5)%, P<0.01]. Decreases in were significantly different between hypocapnia, normocapnia, and hypercapnia (P<0.001). Phenylephrine also caused a significant decrease in CBV during hypocapnia (P<0.01), but not during normocapnia or hypercapnia.
Conclusion
The negative impact of phenylephrine treatment on and CBV is intensified during hypocapnia while blunted during hypercapnia.
doi:10.1093/bja/aes023
PMCID: PMC3325051  PMID: 22391890
carbon dioxide; cerebral blood volume; cerebral tissue oxygen saturation; modulation; phenylephrine
24.  Isoflurane impairs odour discrimination learning in rats: differential effects on short- and long-term memory 
BJA: British Journal of Anaesthesia  2012;108(4):630-637.
Background
Anaesthetics suppress the formation of lasting memories at concentrations that do not suppress perception, but it is unclear which elements of the complex cascade leading from a conscious experience to a lasting memory trace are disrupted. Experiments in conscious humans suggest that subhypnotic concentrations of anaesthetics impair consolidation or maintenance rather than acquisition of a representation (long-term more than short-term memory). We sought to test whether these agents similarly impair learning in rats.
Methods
We used operant conditioning in rats to examine the effect of isoflurane on acquisition compared with long-term (24 h) memory of non-aversive olfactory memories using two different odour discrimination tasks. Rats learned the ‘valences’ of odour pairs presented either separately (task A) or simultaneously (task B), under control conditions and under isoflurane inhalation. In a separate set of experiments, we tested the ability of the animals to recall a learning set that had been acquired 24 h previously.
Results
Under 0.4% isoflurane inhalation, the average number of trials required to reach criterion performance (18 correct responses in 20 successive trials) increased from 21.9 to 43.5 (P<0.05) and 24.2 to 54.4 (P<0.05) for tasks A and B, respectively. Under 0.3% isoflurane inhalation, only task B was impaired (from 24.2 to 31.5 trials, P<0.05). Recall at 24 h was dose-dependently impaired or prevented by isoflurane for both tasks.
Conclusions
Isoflurane interfered with long-term memory of odour valence without preventing its acquisition. This paradigm may serve as a non-aversive animal model of conscious amnesia.
doi:10.1093/bja/aer451
PMCID: PMC3303486  PMID: 22258200
amnesia, anterograde; anaesthetics, general; anaesthetics, inhalation; memory, long term; memory, short term
25.  Short small-interfering RNAs produce interferon-α-mediated analgesia 
BJA: British Journal of Anaesthesia  2012;108(4):662-669.
Background
There is increasing interest in RNA interference in pain research using the intrathecal route to deliver small-interfering RNA (siRNA). An interferon (IFN) response is a common side-effect of siRNA. However, the IFN response in the spinal cord after intrathecal administration of siRNA remains unknown. We hypothesized that high doses of siRNAs can elicit off-target analgesia via releasing IFN-α. We investigated the IFN response and its role in regulating pain sensitivity in the spinal cords after intrathecal administration of siRNAs.
Methods
Male Sprague–Dawley rats were given intrathecal injections of non-targeting (NT) siRNAs or IFN-α and tested for complete Freund's adjuvant (CFA)-induced mechanical allodynia and heat hyperalgesia. IFN-α in the spinal cord after injection of NT siRNAs was measured by western blotting and immunohistochemical staining.
Results
IFN-α was up-regulated in the spinal cord after intrathecal treatment of NT siRNAs. Intrathecal injection of NT siRNAs, at high doses of 10 or 20 μg, reduced CFA-induced inflammatory pain (P<0.05). Intrathecal application of IFN-α inhibited pain hypersensitivity in inflamed rats and produced analgesia in naïve rats (P<0.05). Notably, the anti-nociceptive effects elicited by NT siRNAs and IFN-α were reversed by IFN-α neutralizing antibody and naloxone.
Conclusions
Our data suggest that (i) intrathecal administration of high doses of siRNA (≥10 μg) induced up-regulation of IFN-α in the spinal cord and produced analgesic effects through IFN-α, and (ii) IFN-α's analgesic effect is mediated via opioid receptors. Caution must be taken to avoid IFN-α-mediated analgesic effects of siRNAs in pain research.
doi:10.1093/bja/aer492
PMCID: PMC3303487  PMID: 22307241
analgesia; interferon; small-interfering RNA

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