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26.  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
27.  Failure mode and effects analysis of the universal anaesthesia machine in two tertiary care hospitals in Sierra Leone 
BJA: British Journal of Anaesthesia  2014;113(3):410-415.
Background
Anaesthesia care in developed countries involves sophisticated technology and experienced providers. However, advanced machines may be inoperable or fail frequently when placed into the austere medical environment of a developing country. Failure mode and effects analysis (FMEA) is a method for engaging local staff in identifying real or potential breakdowns in processes or work systems and to develop strategies to mitigate risks.
Methods
Nurse anaesthetists from the two tertiary care hospitals in Freetown, Sierra Leone, participated in three sessions moderated by a human factors specialist and an anaesthesiologist. Sessions were audio recorded, and group discussion graphically mapped by the session facilitator for analysis and commentary. These sessions sought to identify potential barriers to implementing an anaesthesia machine designed for austere medical environments—the universal anaesthesia machine (UAM)—and also engaging local nurse anaesthetists in identifying potential solutions to these barriers.
Results
Participating Sierra Leonean clinicians identified five main categories of failure modes (resource availability, environmental issues, staff knowledge and attitudes, and workload and staffing issues) and four categories of mitigation strategies (resource management plans, engaging and educating stakeholders, peer support for new machine use, and collectively advocating for needed resources).
Conclusions
We identified factors that may limit the impact of a UAM and devised likely effective strategies for mitigating those risks.
doi:10.1093/bja/aeu096
PMCID: PMC4136424  PMID: 24833727
austere anaesthesia; failure mode and effects analysis, FMEA; quality improvement; Sierra Leone
28.  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 
29.  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
30.  Reliability of the American Society of Anesthesiologists physical status scale in clinical practice 
BJA: British Journal of Anaesthesia  2014;113(3):424-432.
Background
Previous studies, which relied on hypothetical cases and chart reviews, have questioned the inter-rater reliability of the ASA physical status (ASA-PS) scale. We therefore conducted a retrospective cohort study to evaluate its inter-rater reliability and validity in clinical practice.
Methods
The cohort included all adult patients (≥18 yr) who underwent elective non-cardiac surgery at a quaternary-care teaching institution in Toronto, Ontario, Canada, from March 2010 to December 2011. We assessed inter-rater reliability by comparing ASA-PS scores assigned at the preoperative assessment clinic vs the operating theatre. We also assessed the validity of the ASA-PS scale by measuring its association with patients' preoperative characteristics and postoperative outcomes.
Results
The cohort included 10 864 patients, of whom 5.5% were classified as ASA I, 42.0% as ASA II, 46.7% as ASA III, and 5.8% as ASA IV. The ASA-PS score had moderate inter-rater reliability (κ 0.61), with 67.0% of patients (n=7279) being assigned to the same ASA-PS class in the clinic and operating theatre, and 98.6% (n=10 712) of paired assessments being within one class of each other. The ASA-PS scale was correlated with patients' age (Spearman's ρ, 0.23), Charlson comorbidity index (ρ=0.24), revised cardiac risk index (ρ=0.40), and hospital length of stay (ρ=0.16). It had moderate ability to predict in-hospital mortality (receiver-operating characteristic curve area 0.69) and cardiac complications (receiver-operating characteristic curve area 0.70).
Conclusions
Consistent with its inherent subjectivity, the ASA-PS scale has moderate inter-rater reliability in clinical practice. It also demonstrates validity as a marker of patients' preoperative health status.
doi:10.1093/bja/aeu100
PMCID: PMC4136425  PMID: 24727705
anaesthesiology; health status; reliability and validity
31.  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
32.  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
33.  Effect of supervised aerobic exercise rehabilitation on physical fitness and quality-of-life in survivors of critical illness: an exploratory minimized controlled trial (PIX study) 
BJA: British Journal of Anaesthesia  2014;113(1):130-137.
Background
Evidence is limited for the effectiveness of interventions for survivors of critical illness after hospital discharge. We explored the effect of an 8-week hospital-based exercise-training programme on physical fitness and quality-of-life.
Methods
In a parallel-group minimized controlled trial, patients were recruited before hospital discharge or in the intensive care follow-up clinic and enrolled 8–16 weeks after discharge. Each week, the intervention comprised two sessions of physiotherapist-led cycle ergometer exercise (30 min, moderate intensity) plus one equivalent unsupervised exercise session. The control group received usual care. The primary outcomes were the anaerobic threshold (in ml O2 kg−1 min−1) and physical function and mental health (SF-36 questionnaire v.2), measured at Weeks 9 (primary time point) and 26. Outcome assessors were blinded to group assignment.
Results
Thirty patients were allocated to the control and 29 to the intervention. For the anaerobic threshold outcome at Week 9, data were available for 17 control vs 13 intervention participants. There was a small benefit (vs control) for the anaerobic threshold of 1.8 (95% confidence interval, 0.4–3.2) ml O2 kg−1 min−1. This advantage was not sustained at Week 26. There was evidence for a possible beneficial effect of the intervention on self-reported physical function at Week 9 (3.4; −1.4 to 8.2 units) and on mental health at Week 26 (4.4; −2.4 to 11.2 units). These potential benefits should be examined robustly in any subsequent definitive trial.
Conclusions
The intervention appeared to accelerate the natural recovery process and seems feasible, but the fitness benefit was only short term.
Clinical trial registration
Current Controlled Trials ISRCTN65176374 (http://www.controlled-trials.com/ISRCTN65176374).
doi:10.1093/bja/aeu051
PMCID: PMC4062299  PMID: 24607602
anaerobic threshold; cardiopulmonary exercise test; rehabilitation, exercise therapy
34.  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
35.  Standardized deceased donor kidney donation rates in the UK reveal marked regional variation and highlight the potential for increasing kidney donation: a prospective cohort study† 
Background
The UK has implemented a national strategy for organ donation that includes a centrally coordinated network of specialist nurses in organ donation embedded in all intensive care units and a national organ retrieval service for deceased organ donors. We aimed to determine whether despite the national approach to donation there is significant regional variation in deceased donor kidney donation rates.
Methods
The UK prospective audit of deaths in critical care was analysed for a cohort of patients who died in critical care between April 2010 and December 2011. Multivariate logistic regression was used to identify the factors associated with kidney donation. The logistic regression model was then used to produce risk-adjusted funnel plots describing the regional variation in donation rates.
Results
Of the 27 482 patients who died in a critical care setting, 1528 (5.5%) became kidney donors. Factors found to influence donation rates significantly were: type of critical care [e.g. neurointensive vs general intensive care: OR 1.53, 95% confidence interval (CI) 1.34–1.75, P<0.0001], patient ethnicity (e.g. ‘Asian’ vs ‘white’: OR 0.17, 95% CI 0.11–0.26, P<0.0001), age (e.g. age >69 vs age 18–39 yr: OR 0.2, 0.15–0.25, P<0.0001), and cause of death [e.g. ‘other’ (excluding ‘stroke’ and ‘trauma’) vs ‘trauma’: OR 0.04, 95% CI 0.03–0.05, P<0.0001]. Despite correction for these variables, kidney donation rates for the 20 UK kidney donor regions showed marked variation. The overall standardized donation rate ranged from 3.2 to 7.5%. Four regions had donation rates of >2 standard deviations (sd) from the mean (two below and two above). Regional variation was most marked for donation after circulatory death (DCD) kidney donors with 9 of the 20 regions demonstrating donation rates of >2 sd from the mean (5 below and 4 above).
Conclusions
The marked regional variation in kidney donation rates observed in this cohort after adjustment for factors strongly associated with donation rates suggests that there is considerable scope for further increasing kidney donation rates in the UK, particularly DCD.
doi:10.1093/bja/aet473
PMCID: PMC4062298  PMID: 24335581
donors, organ transplantation; kidney, transplantation; model, statistical; surgery, transplantation; transplantation, kidney
36.  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
37.  Predictive performance of the Domino, Hijazi, and Clements models during low-dose target-controlled ketamine infusions in healthy volunteers 
British journal of anaesthesia  2007;98(5):10.1093/bja/aem063.
Background
Healthy volunteers received low-dose target-controlled infusions (TCI) of ketamine controlled by the Domino model while cognitive function tests and functional neuroimaging were performed. The aim of the current study was to assess the predictive performance of the Domino model during these studies, and compare it with that of three other ketamine models.
Methods
Fifty-eight volunteers received ketamine administered by a TCI device on one or more occasions at target concentrations of either 50, 100, or 200 ng ml−1. At each target concentration, two or three venous blood samples were withdrawn during infusion, with a further sample after the infusion ended. Ketamine assays were performed by gas chromatography. The plasma concentration time courses predicted by the Hijazi, Clements 125, and Clements 250 models were calculated retrospectively, and the predictive performance of each of the models was assessed using Varvel methodology.
Results
For the Domino model, bias, inaccuracy, wobble, and divergence were −2.7%, 33.9%, 24.2%, and 0.1463 % h−1, respectively. There was a systematic increase in performance error over time. The Clements 250 model performed best by all criteria, whereas the Hijazi model performed least well by all criteria except for bias.
Conclusions
Performance of the Domino model during control of low-dose ketamine infusions was sub-optimal. The Clements 250 model may be a better model for controlling low-dose TCI ketamine administration
doi:10.1093/bja/aem063
PMCID: PMC3838936  PMID: 17389691
anaesthetics; i.v.; ketamine; pharmacokinetics
38.  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
39.  Activation of K2P channel–TREK1 mediates the neuroprotection induced by sevoflurane preconditioning 
BJA: British Journal of Anaesthesia  2013;113(1):157-167.
Background
Preconditioning with volatile anaesthetic agents induces tolerance to focal cerebral ischaemia, although the underlying mechanisms have not been clearly defined. The present study analyses whether TREK-1, a two-pore domain K+ channel and target for volatile anaesthetics, plays a role in mediating neuroprotection by sevoflurane.
Methods
Differentiated SH-SY5Y cells were preconditioning with sevoflurane and challenged by oxygen–glucose deprivation (OGD). Cell viability and expression of caspase-3 and TREK-1 were evaluated. Rats that were preconditioned with sevoflurane were subjected to middle cerebral artery occlusion (MCAO), and the expression of TREK-1 protein and mRNA was analysed. Neurological scores were evaluated and infarction volume was examined.
Results
Sevoflurane preconditioning reduced cell death in differentiated SH-SY5Y cells challenged by OGD. Sevoflurane preconditioning reduced infarct volume and improved neurological outcome in rats subjected to MCAO. Sevoflurane preconditioning increased levels of TREK-1 mRNA and protein. Knockdown of TREK-1 significantly attenuated sevoflurane preconditioning-induced neuroprotective effects in vitro and in vivo.
Conclusions
Sevoflurane preconditioning-induced neuroprotective effects against transient cerebral ischaemic injuries involve TREK-1 channels. These results suggest a novel mechanism for sevoflurane preconditioning-induced tolerance to focal cerebral ischaemia.
doi:10.1093/bja/aet338
PMCID: PMC4062297  PMID: 24154701
anaesthetics volatile, sevoflurane; brain, ischaemia; neuroprotection; preconditioning; TREK-1
40.  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
41.  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
42.  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
43.  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
44.  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
45.  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
46.  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
47.  Impact of the World Health Organization's Surgical Safety Checklist on safety culture in the operating theatre: a controlled intervention study 
BJA: British Journal of Anaesthesia  2013;110(5):807-815.
Background
Positive changes in safety culture have been hypothesized to be one of the mechanisms behind the reduction in mortality and morbidity after the introduction of the World Health Organization's Surgical Safety Checklist (SSC). We aimed to study the checklist effects on safety culture perceptions in operating theatre personnel using a prospective controlled intervention design at a single Norwegian university hospital.
Methods
We conducted a study with pre- and post-intervention surveys using the intervention and control groups. The primary outcome was the effects of the Norwegian version of the SSC on safety culture perceptions. Safety culture was measured using the validated Norwegian version of the Hospital Survey on Patient Safety Culture. Descriptive characteristics of operating theatre personnel and checklist compliance data were also recorded. A mixed linear regression model was used to assess changes in safety culture.
Results
The response rate was 61% (349/575) at baseline and 51% (292/569) post-intervention. Checklist compliance ranged from 77% to 85%. We found significant positive changes in the checklist intervention group for the culture factors ‘frequency of events reported’ and ‘adequate staffing’ with regression coefficients at −0.25 [95% confidence interval (CI), −0.47 to −0.07] and 0.21 (95% CI, 0.07–0.35), respectively. Overall, the intervention group reported significantly more positive culture scores—including at baseline.
Conclusions
Implementation of the SSC had rather limited impact on the safety culture within this hospital.
doi:10.1093/bja/aet005
PMCID: PMC3630285  PMID: 23404986
checklist; safety; safety climate; safety culture; surgery
48.  Time course of haemostatic effects of fibrinogen concentrate administration in aortic surgery 
BJA: British Journal of Anaesthesia  2013;110(6):947-956.
Background
There is currently a contrast between the demonstrated benefits of fibrinogen concentrate in correcting bleeding and reducing transfusion, and its perceived thrombogenic potential. This analysis evaluates the effects of fibrinogen concentrate on coagulation up to 12 days after administration during aortic surgery.
Methods
We performed a post hoc analysis of a prospective, randomized, double-blind, controlled trial of fibrinogen concentrate as first-line haemostatic therapy in aortic surgery. After cardiopulmonary bypass (CPB) and protamine administration, subjects with coagulopathic bleeding received fibrinogen concentrate or placebo. The placebo group received allogeneic blood products, including fresh-frozen plasma (FFP; n=32); the fibrinogen concentrate group received fibrinogen concentrate alone (FC; n=14), or fibrinogen concentrate followed by allogeneic blood products (FC+FFP; n=15). Plasma fibrinogen, fibrin-based clotting (ROTEM®-based FIBTEM assay), and peri- and postoperative haematological and coagulation parameters were compared.
Results
Plasma fibrinogen and FIBTEM maximum clot firmness (MCF) decreased ∼50% during CPB but were corrected by FC or FC+FFP. At last suture, the highest values for plasma fibrinogen (360 mg dl−1) and FIBTEM MCF (22 mm) were within normal ranges—below the acute phase increases observed after surgery. In patients receiving only FFP as a source of fibrinogen, these parameters recovered marginally by last suture (P<0.001 vs FC and FC+FFP). All groups displayed comparable haemostasis at 24 h post-surgery. Fibrinogen concentrate did not cause alterations of other haemostasis parameters.
Conclusions
Fibrinogen concentrate provided specific, significant, short-lived increases in plasma fibrinogen and fibrin-based clot firmness after aortic surgery.
doi:10.1093/bja/aes576
PMCID: PMC3657602  PMID: 23388508
blood coagulation tests; cardiopulmonary bypass; fibrin; fibrinogen; plasma
49.  Antioxidants that protect mitochondria reduce interleukin-6 and oxidative stress, improve mitochondrial function, and reduce biochemical markers of organ dysfunction in a rat model of acute sepsis 
BJA: British Journal of Anaesthesia  2013;110(3):472-480.
Background
Sepsis-induced organ failure is the major cause of death in critical care units, and is characterized by a massive dysregulated inflammatory response and oxidative stress. We investigated the effects of treatment with antioxidants that protect mitochondria (MitoQ, MitoE, or melatonin) in a rat model of lipopolysaccharide (LPS) plus peptidoglycan (PepG)-induced acute sepsis, characterized by inflammation, mitochondrial dysfunction and early organ damage.
Methods
Anaesthetized and ventilated rats received an i.v. bolus of LPS and PepG followed by an i.v. infusion of MitoQ, MitoE, melatonin, or saline for 5 h. Organs and blood were then removed for determination of mitochondrial and organ function, oxidative stress, and key cytokines.
Results
MitoQ, MitoE, or melatonin had broadly similar protective effects with improved mitochondrial respiration (P<0.002), reduced oxidative stress (P<0.02), and decreased interleukin-6 levels (P=0.0001). Compared with control rats, antioxidant-treated rats had lower levels of biochemical markers of organ dysfunction, including plasma alanine amino-transferase activity (P=0.02) and creatinine concentrations (P<0.0001).
Conclusions
Antioxidants that act preferentially in mitochondria reduce mitochondrial damage and organ dysfunction and decrease inflammatory responses in a rat model of acute sepsis.
doi:10.1093/bja/aes577
PMCID: PMC3570068  PMID: 23381720
co-enzyme Q10; interleukin-6; interleukin-10; melatonin; sepsis; tocopherol
50.  Haemostatic monitoring during postpartum haemorrhage and implications for management 
BJA: British Journal of Anaesthesia  2012;109(6):851-863.
Summary
Postpartum haemorrhage (PPH) is a major risk factor for maternal morbidity and mortality. PPH has numerous causative factors, which makes its occurrence and severity difficult to predict. Underlying haemostatic imbalances such as consumptive and dilutional coagulopathies may develop during PPH, and can exacerbate bleeding and lead to progression to severe PPH. Monitoring coagulation status in patients with PPH may be crucial for effective haemostatic management, goal-directed therapy, and improved outcomes. However, current PPH management guidelines do not account for the altered baseline coagulation status observed in pregnant patients, and the appropriate transfusion triggers to use in PPH are unknown, due to a lack of high-quality studies specific to this area. In this review, we consider the evidence for the use of standard laboratory-based coagulation tests and point-of-care viscoelastic coagulation monitoring in PPH. Many laboratory-based tests are unsuitable for emergency use due to their long turnaround times, so have limited value for the management of PPH. Emerging evidence suggests that viscoelastic monitoring, using thrombelastography- or thromboelastometry-based tests, may be useful for rapid assessment and for guiding haemostatic therapy during PPH. However, further studies are needed to define the ranges of reference values that should be considered ‘normal’ in this setting. Improving awareness of the correct application and interpretation of viscoelastic coagulation monitoring techniques may be critical in realizing their emergency diagnostic potential.
doi:10.1093/bja/aes361
PMCID: PMC3498756  PMID: 23075633
blood coagulation tests; point-of-care systems; postpartum haemorrhage; thrombelastography

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