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1.  Understanding outcomes after neuraxial anaesthesia: time to turn the page 
doi:10.1093/bja/aev353
PMCID: PMC4681617  PMID: 26487154
2.  Neuraxial block and postoperative epidural analgesia: effects on outcomes in the POISE-2 trial† 
BJA: British Journal of Anaesthesia  2015;116(1):100-112.
Background. We assessed associations between intraoperative neuraxial block and postoperative epidural analgesia, and a composite primary outcome of death or non-fatal myocardial infarction, at 30 days post-randomization in POISE-2 Trial subjects.
Methods. 10 010 high-risk noncardiac surgical patients were randomized aspirin or placebo and clonidine or placebo. Neuraxial block was defined as intraoperative spinal anaesthesia, or thoracic or lumbar epidural anaesthesia. Postoperative epidural analgesia was defined as postoperative epidural local anaesthetic and/or opioid administration. We used logistic regression with weighting using estimated propensity scores.
Results. Neuraxial block was not associated with the primary outcome [7.5% vs 6.5%; odds ratio (OR), 0.89; 95% CI (confidence interval), 0.73–1.08; P=0.24], death (1.0% vs 1.4%; OR, 0.84; 95% CI, 0.53–1.35; P=0.48), myocardial infarction (6.9% vs 5.5%; OR, 0.91; 95% CI, 0.74–1.12; P=0.36) or stroke (0.3% vs 0.4%; OR, 1.05; 95% CI, 0.44–2.49; P=0.91). Neuraxial block was associated with less clinically important hypotension (39% vs 46%; OR, 0.90; 95% CI, 0.81–1.00; P=0.04). Postoperative epidural analgesia was not associated with the primary outcome (11.8% vs 6.2%; OR, 1.48; 95% CI, 0.89–2.48; P=0.13), death (1.3% vs 0.8%; OR, 0.84; 95% CI, 0.35–1.99; P=0.68], myocardial infarction (11.0% vs 5.7%; OR, 1.53; 95% CI, 0.90–2.61; P=0.11], stroke (0.4% vs 0.4%; OR, 0.65; 95% CI, 0.18–2.32; P=0.50] or clinically important hypotension (63% vs 36%; OR, 1.40; 95% CI, 0.95–2.09; P=0.09).
Conclusions. Neuraxial block and postoperative epidural analgesia were not associated with adverse cardiovascular outcomes among POISE-2 subjects.
doi:10.1093/bja/aev255
PMCID: PMC4681616  PMID: 26209855
anaesthesia, epidural; anaesthesia, spinal; death; myocardial infarction; stroke
3.  Evidence of an association between brain cellular injury and cognitive decline after non-cardiac surgery 
Background. Postoperative cognitive dysfunction (POCD) is common after non-cardiac surgery, but the mechanism is unclear. We hypothesized that decrements in cognition 1 month after non-cardiac surgery would be associated with evidence of brain injury detected by elevation of plasma concentrations of S100β, neuron-specific enolase (NSE), and/or the brain-specific protein glial fibrillary acid protein (GFAP).
Methods. One hundred and forty-nine patients undergoing shoulder surgery underwent neuropsychological testing before and then 1 month after surgery. Plasma was collected before and after anaesthesia. We determined the relationship between plasma biomarker concentrations and individual neuropsychological test results and a composite cognitive functioning score (mean Z-score).
Results. POCD (≥−1.5 sd decrement in Z-score from baseline) was present in 10.1% of patients 1 month after surgery. There was a negative relationship between higher plasma GFAP concentrations and lower postoperative composite Z-scores {estimated slope=−0.14 [95% confidence interval (CI) −0.24 to −0.04], P=0.005} and change from baseline in postoperative scores on the Rey Complex Figure Test copy trial (P=0.021), delayed recall trial (P=0.010), and the Symbol Digit Modalities Test (P=0.004) after adjustment for age, sex, history of hypertension and diabetes. A similar relationship was not observed with S100β or NSE concentrations.
Conclusions. Decline in cognition 1 month after shoulder surgery is associated with brain cellular injury as demonstrated by elevated plasma GFAP concentrations.
doi:10.1093/bja/aev415
PMCID: PMC4681618  PMID: 26675953
brain injury biomarkers; non-cardiac surgery; postoperative cognitive dysfunction
4.  Controversies in anaesthesia for noncardiac surgery in older adults 
BJA: British Journal of Anaesthesia  2015;115(Suppl 2):ii15-ii25.
As the population of the world is rapidly ageing, the amount of surgery being performed in older patients is also increasing. Special attention is required for the anaesthetic and perioperative management of these patients. The clinical and non-clinical issues specific to older surgical patients are reviewed, with a special emphasis on areas of debate related to anaesthesia care in this group. These issues include the role of frailty and disability in preoperative assessment, choice of anaesthesia technique for hip fracture, postoperative delirium, and approaches to shared decision-making before surgical procedures.
doi:10.1093/bja/aev396
PMCID: PMC4809989  PMID: 26658197
ageing; anaesthesia; frail elderly; geriatric anaesthesia; hip fracture
6.  Neurobehavioural abnormalities induced by repeated exposure of neonatal rats to sevoflurane can be aggravated by social isolation and enrichment deprivation initiated after exposure to the anaesthetic 
BJA: British Journal of Anaesthesia  2015;115(5):752-760.
Background
We tested the hypothesis that developmental effects of repeated neonatal exposure to sevoflurane in rats are exacerbated by stressful experiences received later in life.
Methods
Sprague-Dawley male rats received sequential exposures to 3% sevoflurane for two h on postnatal days (P) six, seven, and eight. After weaning at P21, rats were housed either in pairs in an enriched environment (EE) or singly in an enrichment-deprived environment (an adverse environment, AE). The hippocampal concentrations of brain-derived neurotrophic factor (BDNF), and synaptic markers were assessed at P8 and P53. The dentate gyrus neural progenitor proliferation was evaluated at P11 and P53 after administration of bromodeoyuridine (BrdU) at P8 to P10 and at P22 to P27, respectively. Neurobehavioural evaluations were performed at P49 to P53.
Results
Repeated sevoflurane exposure acutely reduced concentrations of BDNF, synaptic markers and neural progenitor proliferation. The sevoflurane group housed in the AE conditions (sevoflurane+AE) had decreased concentrations of BDNF and synaptic markers, and survival of new granule cells and impaired cognitive function compared with the control+AE, control+EE, and sevoflurane+EE groups. The neurobehavioural parameters in the sevoflurane+EE and control+EE groups were similar.
Conclusions
Neurocognitive abnormalities induced by repeated neonatal exposure to sevoflurane can be aggravated by stressful conditions such as social isolation and enrichment deprivation.
doi:10.1093/bja/aev339
PMCID: PMC4608490  PMID: 26475803
brain-derived neurotrophic factor; cognition; environment; rats; sevoflurane; social isolation
7.  Clinically relevant concentrations of lidocaine and ropivacaine inhibit TNFα-induced invasion of lung adenocarcinoma cells in vitro by blocking the activation of Akt and focal adhesion kinase 
BJA: British Journal of Anaesthesia  2015;115(5):784-791.
Background
Matrix-metalloproteinases (MMP) and cancer cell invasion are crucial for solid tumour metastasis. Important signalling events triggered by inflammatory cytokines, such as tumour necrosis factor α (TNFα), include Src-kinase-dependent activation of Akt and focal adhesion kinase (FAK) and phosphorylation of caveolin-1. Based on previous studies where we demonstrated amide-type local anaesthetics block TNFα-induced Src activation in malignant cells, we hypothesized that local anaesthetics might also inhibit the activation and/or phosphorylation of Akt, FAK and caveolin-1, thus attenuating MMP release and invasion of malignant cells.
Methods
NCI-H838 lung adenocarcinoma cells were incubated with ropivacaine or lidocaine (1 nM-100 µM) in absence/presence of TNFα (20 ng ml−1) for 20 min or 4 h, respectively. Activation/phosphorylation of Akt, FAK and caveolin-1 were evaluated by Western blot, and MMP-9 secretion was determined by enzyme-linked immunosorbent assay. Tumour cell migration (electrical wound-healing assay) and invasion were also assessed.
Results
Ropivacaine (1 nM–100 μM) and lidocaine (1–100 µM) significantly reduced TNFα-induced activation/phosphorylation of Akt, FAK and caveolin-1 in NCI-H838 cells. MMP-9 secretion triggered by TNFα was significantly attenuated by both lidocaine and ropivacaine (half-maximal inhibitory concentration [IC50]=3.29×10−6 M for lidocaine; IC50=1.52×10−10 M for ropivacaine). The TNFα-induced increase in invasion was completely blocked by both lidocaine (10 µM) and ropivacaine (1 µM).
Conclusions
At clinically relevant concentrations both ropivacaine and lidocaine blocked tumour cell invasion and MMP-9 secretion by attenuating Src-dependent inflammatory signalling events. Although determined entirely in vitro, these findings provide significant insight into the potential mechanism by which local anaesthetics might diminish metastasis.
doi:10.1093/bja/aev341
PMCID: PMC4850926  PMID: 26475807
anesthetics, local; inflammation; neoplasm metastasis
8.  Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries 
BJA: British Journal of Anaesthesia  2016;117(5):601-609.
Background: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care.
Methods: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries.
Results: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2–7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries.
Conclusions: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care.
Study registration: ISRCTN51817007
doi:10.1093/bja/aew316
PMCID: PMC5091334  PMID: 27799174
cohort studies; critical care/utilisation; operative/mortality; postoperative care/methods; postoperative care/statistics and numerical data; surgery; surgical procedures
9.  High PEEP in acute respiratory distress syndrome: quantitative evaluation between improved arterial oxygenation and decreased oxygen delivery 
BJA: British Journal of Anaesthesia  2016;117(5):650-658.
Background. Positive end-expiratory pressure (PEEP) is widely used to improve oxygenation and prevent alveolar collapse in mechanically ventilated patients with the acute respiratory distress syndrome (ARDS). Although PEEP improves arterial oxygenation predictably, high-PEEP strategies have demonstrated equivocal improvements in ARDS-related mortality. The effect of PEEP on tissue oxygen delivery is poorly understood and is difficult to quantify or investigate in the clinical environment.
Methods. We investigated the effects of PEEP on tissue oxygen delivery in ARDS using a new, high-fidelity, computational model with highly integrated respiratory and cardiovascular systems. The model was configured to replicate published clinical trial data on the responses of 12 individual ARDS patients to changes in PEEP. These virtual patients were subjected to increasing PEEP levels during a lung-protective ventilation strategy (0–20 cm H2O). Measured variables included arterial oxygenation, cardiac output, peripheral oxygen delivery, and alveolar strain.
Results. As PEEP increased, tissue oxygen delivery decreased in all subjects (mean reduction of 25% at 20 cm H2O PEEP), despite an increase in arterial oxygen tension (mean increase 6.7 kPa at 20 cm H2O PEEP). Changes in arterial oxygenation and tissue oxygen delivery differed between subjects but showed a consistent pattern. Static and dynamic alveolar strain decreased in all patients as PEEP increased.
Conclusions. Incremental PEEP in ARDS appears to protect alveoli and improve arterial oxygenation, but also appears to impair tissue oxygen delivery significantly because of reduced cardiac output. We propose that this trade-off may explain the poor improvements in mortality associated with high-PEEP ventilation strategies.
doi:10.1093/bja/aew314
PMCID: PMC5091333  PMID: 27799180
computer simulation; respiration, artificial; respiratory distress syndrome, adult
10.  The Effect of patient warming during Caesarean delivery on maternal and neonatal outcomes: a meta-analysis 
BJA: British Journal of Anaesthesia  2015;115(4):500-510.
Background
Perioperative warming is recommended for surgery under anaesthesia, however its role during Caesarean delivery remains unclear. This meta-analysis aimed to determine the efficacy of active warming on outcomes after elective Caesarean delivery.
Methods
We searched databases for randomized controlled trials utilizing forced air warming or warmed fluid within 30 min of neuraxial anaesthesia placement. Primary outcome was maximum temperature change. Secondary outcomes included maternal (end of surgery temperature, shivering, thermal comfort, hypothermia) and neonatal (temperature, umbilical cord pH and Apgar scores) outcomes. Standardized mean difference/mean difference/risk ratio (SMD/MD/RR) and 95% confidence interval (CI) were calculated using random effects modelling (CMA, version 2, 2005).
Results
13 studies met our criteria and 789 patients (416 warmed and 373 controls) were analysed for the primary outcome. Warming reduced temperature change (SMD −1.27°C [−1.86, −0.69]; P=0.00002); resulted in higher end of surgery temperatures (MD 0.43 °C [0.27, 0.59]; P<0.00001); was associated with less shivering (RR 0.58 [0.43, 0.79]; P=0.0004); improved thermal comfort (SMD 0.90 [0.36, 1.45]; P=0.001), and decreased hypothermia (RR 0.66 [0.50, 0.87]; P=0.003). Umbilical artery pH was higher in the warmed group (MD 0.02 [0, 0.05]; P=0.04). Egger's test (P=0.001) and contour-enhanced funnel plot suggest a risk of publication bias for the primary outcome of temperature change.
Conclusions
Active warming for elective Caesarean delivery decreases perioperative temperature reduction and the incidence of hypothermia and shivering. These findings suggest that forced air warming or warmed fluid should be used for elective Caesarean delivery.
doi:10.1093/bja/aev325
PMCID: PMC4574493  PMID: 26385660
anaesthesia; body temperature, hypothermia; caesarean section; obstetric; temperature
11.  Ex vivo reversal of effects of rivaroxaban evaluated using thromboelastometry and thrombin generation assay 
BJA: British Journal of Anaesthesia  2016;117(5):583-591.
Background
In major bleeding events, the new direct oral anticoagulants pose a great challenge for physicians. The aim of the study was to test for ex vivo reversal of the direct oral anticoagulant rivaroxaban with various non-specific reversal agents: prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (aPCC), recombinant activated factor VII (rFVIIa), and fibrinogen concentrate (FI).
Methods
Blood was obtained from healthy volunteers and from patients treated with rivaroxaban. Blood samples from healthy volunteers were spiked with rivaroxaban to test the correlation between rivaroxaban concentration and coagulation tests. Patient blood samples were spiked with various concentrations of the above-mentioned agents and analysed using thromboelastometry and thrombin generation.
Results
When added in vitro, rivaroxaban was significantly (P<0.05) correlated with ROTEM® thromboelastometry EXTEM (extrinsic coagulation pathway) clotting time (CT), time to maximal velocity (MaxV−t), and with all measured thrombin generation parameters. In vivo, CT, MaxV−t, lag time, and peak thrombin generation (Cmax) were significantly correlated with rivaroxaban concentrations. Regarding reversal of rivaroxaban, all tested agents significantly (P<0.05) reduced EXTEM CT, but to different extents: rFVIIa by 68%, aPCC by 47%, PCC by 17%, and FI by 9%. Only rFVIIa reversed EXTEM CT to baseline values. Both PCC (+102%) and aPCC (+232%) altered overall thrombin generation (area under the curve) and increased Cmax (+461% for PCC, +87.5% for aPCC).
Conclusions
Thromboelastometry and thrombin generation assays do not favour the same reversal agents for rivaroxaban anticoagulation. Controlled clinical trials are urgently needed to establish doses and clinical efficacy of potential reversal agents.
Clinical trial registration
EudracCT trial no. 213-00474-30.
doi:10.1093/bja/aew259
PMCID: PMC5091332  PMID: 27623677
blood, anticoagulants; complications, haemorrhage; thromboelastography
12.  Emergence from general anaesthesia and evolution of delirium signs in the post-anaesthesia care unit 
BJA: British Journal of Anaesthesia  2014;115(3):411-417.
Background
Emergence from anaesthesia is often accompanied by signs of delirium, including fluctuating mental status and inattention. The evolution of these signs of delirium requires investigation since delirium in the post-anaesthesia care unit (PACU) may be associated with worse outcomes.
Methods
Adult patients emerging from anaesthesia were assessed for agitated emergence in the operating room using the Richmond Agitation-Sedation Scale (RASS). The Confusion Assessment Method for the Intensive Care Unit was then used to evaluate delirium signs at PACU admission and during PACU stay at 30 min, 1 h, and discharge. Signs consistent with delirium were classified as hyperactive vs hypoactive based upon a positive CAM-ICU assessment and the concomitant RASS score. Multivariable logistic regression was utilized to assess potential risk factors for delirium during PACU stay including age, American Society of Anesthesiologists classification, and opioid and benzodiazepine exposure.
Results
Among 400 patients enrolled, 19% had agitated emergence. Delirium signs were present at PACU admission, 30 min, 1 h, and PACU discharge in 124 (31%), 59 (15%), 32 (8%), and 15 (4%) patients, respectively. In patients with delirium signs, hypoactive signs were present in 56% at PACU admission and in 92% during PACU stay. Perioperative opioids were associated with delirium signs during PACU stay (P=0.02).
Conclusions
A significant proportion of patients develop delirium signs in the immediate postoperative period, primarily manifesting with a hypoactive subtype. These signs often persist to PACU discharge, suggesting the need for structured delirium monitoring in the PACU to identify patients potentially at risk for worse outcomes in the postoperative period.
doi:10.1093/bja/aeu442
PMCID: PMC4533730  PMID: 25540068
anaesthesia; complications; delirium
13.  Intraoperative hypotension and delirium after on-pump cardiac surgery† 
BJA: British Journal of Anaesthesia  2015;115(3):427-433.
Background
Delirium is a common complication after cardiac surgery and may be as a result of inadequate cerebral perfusion. We studied delirium after cardiac surgery in relation to intraoperative hypotension (IOH).
Methods
This observational single-centre, cohort study was nested in a randomized trial, on a single intraoperative dose of dexamethasone vs placebo during cardiac surgery. During the first four postoperative days, patients were screened for delirium based on the Confusion Assessment Method (CAM) for Intensive Care Unit on the intensive care unit, CAM on the ward, and by inspection of medical records. To combine depth and duration of IOH, we computed the area under the curve for four blood pressure thresholds. Logistic regression analyses were performed to investigate the association between IOH and the occurrence of postoperative delirium, adjusting for confounding and using a 99% confidence interval to correct for multiple testing.
Results
Of the 734 included patients, 99 patients (13%) developed postoperative delirium. The adjusted Odds Ratio for the Mean Arterial Pressure <60 mm Hg threshold was 1.04 (99% confidence interval: 0.99–1.10) for each 1000 mm Hg2 min2 AUC2 increase. IOH, as defined according to the other three definitions, was not associated with postoperative delirium either. Deep and prolonged IOH seemed to increase the risk of delirium, but this was not statistically significant.
Conclusions
Independent of the applied definition, IOH was not associated with the occurrence of delirium after cardiac surgery.
doi:10.1093/bja/aev256
PMCID: PMC4635646  PMID: 26209856
cardiac surgical procedures; delirium dementia, amnestic cognitive disorders; hypotension
14.  Impact of intraoperative hypotension and blood pressure fluctuations on early postoperative delirium after non-cardiac surgery†‡ 
BJA: British Journal of Anaesthesia  2015;115(3):418-426.
Introduction
Postoperative delirium is common in older patients. Despite its prognostic significance, the pathophysiology is incompletely understood. Although many risk factors have been identified, no reversible factors, particularly ones potentially modifiable by anaesthetic management, have been identified. The goal of this prospective cohort study was to investigate whether intraoperative hypotension was associated with postoperative delirium in older patients undergoing major non-cardiac surgery.
Methods
Study subjects were patients >65 years of age, undergoing major non-cardiac surgery, who were enrolled in an ongoing prospective observational study of the pathophysiology of postoperative delirium. Intraoperative blood pressure was measured and predefined criteria were used to define hypotension. Delirium was measured by the Confusion Assessment Method on the first two postoperative days. Data were analysed using t-tests, two-sample proportion tests and ordered logistic regression multivariable models, including correction for multiple comparisons.
Results
Data from 594 patients with a mean age of 73.6 years (sd 6.2) were studied. Of these 178 (30%) developed delirium on day 1 and 176 (30%) on day 2. Patients developing delirium were older, more often female, had lower preoperative cognitive scores, and underwent longer operations. Relative hypotension (decreases by 20, 30, or 40%) or absolute hypotension [mean arterial pressure (MAP)<50 mm Hg] were not significantly associated with postoperative delirium, nor was the duration of hypotension (MAP<50 mm Hg). Conversely, intraoperative blood pressure variance was significantly associated with postoperative delirium.
Discussion
These results showed that increased blood pressure fluctuation, not absolute or relative hypotension, was predictive of postoperative delirium.
doi:10.1093/bja/aeu458
PMCID: PMC4533731  PMID: 25616677
arterial blood pressure; delirium; hypotension
15.  Mode of anaesthesia for preterm Caesarean delivery: secondary analysis from the Maternal–Fetal Medicine Units Network Caesarean Registry†‡ 
BJA: British Journal of Anaesthesia  2015;115(2):267-274.
Background
Preterm delivery is often performed by Caesarean section. We investigated modes of anaesthesia and risk factors for general anaesthesia among women undergoing preterm Caesarean delivery.
Methods
Women undergoing Caesarean delivery between 24+0 and 36+6 weeks' gestation were identified from a multicentre US registry. The mode of anaesthesia was classified as neuraxial anaesthesia (spinal, epidural, or combined spinal and epidural) or general anaesthesia. Logistic regression was used to identify patient characteristic, obstetric, and peripartum risk factors associated with general anaesthesia.
Results
Within the study cohort, 11 539 women had preterm Caesarean delivery; 9510 (82.4%) underwent neuraxial anaesthesia and 2029 (17.6%) general anaesthesia. In our multivariate model, African-American race [adjusted odds ratio (aOR)=1.9; 95% confidence interval (CI)=1.7–2.2], Hispanic ethnicity (aOR=1.5; 95% CI=1.2–1.8), other race (aOR=1.4; 95% CI=1.1–1.9), and haemolysis, elevated liver enzymes and low platelets (HELLP) syndrome or eclampsia (aOR=2.8; 95% CI=2.2–3.5) were independently associated with receiving general anaesthesia for preterm Caesarean delivery. Women with an emergency Caesarean delivery indication had the highest odds for general anaesthesia (aOR=3.5; 95% CI=3.1–3.9). For every 1 week decrease in gestational age at delivery, the adjusted odds of general anaesthesia increased by 13%.
Conclusions
In our study cohort, nearly one in five women received general anaesthesia for preterm Caesarean delivery. Although potential confounding by unmeasured factors cannot be excluded, our findings suggest that early gestational age at delivery, emergent Caesarean delivery indications, hypertensive disease, and non-Caucasian race or ethnicity are associated with general anaesthesia for preterm Caesarean delivery.
doi:10.1093/bja/aev108
PMCID: PMC4500761  PMID: 25956901
anaesthesia; Caesarean; preterm
16.  Pregabalin and pain after total knee arthroplasty: a double-blind, randomized, placebo-controlled, multidose trial† 
BJA: British Journal of Anaesthesia  2015;115(2):285-293.
Background
Pregabalin may reduce postoperative pain and opioid use. Higher doses may be more effective, but may cause sedation and confusion. This prospective, randomized, blinded, placebo-controlled study tested the hypothesis that pregabalin reduces pain at 2 weeks after total knee arthroplasty, but increases drowsiness and confusion.
Methods
Patients (30 per group) received capsules containing pregabalin (0, 50, 100, or 150 mg); two capsules before surgery, one capsule twice a day until postoperative day (POD) 14, one on POD15, and one on POD16. Multimodal analgesia included femoral nerve block, epidural analgesia, oxycodone–paracetamol, and meloxicam. The primary outcome was pain with flexion (POD14).
Results
Pregabalin did not reduce pain at rest, with ambulation, or with flexion at 2 weeks (P=0.69, 0.23, and 0.90, respectively). Pregabalin increased POD1 drowsiness (34.5, 37.9, 55.2, and 58.6% in the 0, 50, 100, and 150 mg arms, respectively; P=0.030), but did not increase confusion (0, 3.5, 0, and 3.5%, respectively; P=0.75). Pregabalin had no effect on acute or chronic pain, opioid consumption, or analgesic side-effects. Pregabalin reduced POD14 patient satisfaction [1–10 scale, median (first quartile, third quartile): 9 (8, 10), 8 (7, 10), 8 (5, 9), and 8 (6, 9.3), respectively; P=0.023). Protocol compliance was 63% by POD14 (50.0, 70.0, 76.7, and 56.7% compliance, respectively), with no effect of dose on compliance. Per-protocol analysis of compliant patients showed no effect of pregabalin on pain scores.
Conclusions
Pregabalin had no beneficial effects, but increased sedation and decreased patient satisfaction. This study does not support routine perioperative pregabalin for total knee arthroplasty patients.
Clinical trial registration.
ClinicalTrials.gov: http://www.clinicaltrials.gov/ct2/show/study/NCT01333956.
doi:10.1093/bja/aev217
PMCID: PMC4500762  PMID: 26170351
analgesia; anticonvulsants; arthroplasty; knee; pain management; perioperative care; replacement
17.  Cell-Based therapy for traumatic brain injury 
BJA: British Journal of Anaesthesia  2015;115(2):203-212.
Traumatic brain injury is a major economic burden to hospitals in terms of emergency department visits, hospitalizations, and utilization of intensive care units. Current guidelines for the management of severe traumatic brain injuries are primarily supportive, with an emphasis on surveillance (i.e. intracranial pressure) and preventive measures to reduce morbidity and mortality. There are no direct effective therapies available. Over the last fifteen years, pre-clinical studies in regenerative medicine utilizing cell-based therapy have generated enthusiasm as a possible treatment option for traumatic brain injury. In these studies, stem cells and progenitor cells were shown to migrate into the injured brain and proliferate, exerting protective effects through possible cell replacement, gene and protein transfer, and release of anti-inflammatory and growth factors. In this work, we reviewed the pathophysiological mechanisms of traumatic brain injury, the biological rationale for using stem cells and progenitor cells, and the results of clinical trials using cell-based therapy for traumatic brain injury. Although the benefits of cell-based therapy have been clearly demonstrated in pre-clinical studies, some questions remain regarding the biological mechanisms of repair and safety, dose, route and timing of cell delivery, which ultimately will determine its optimal clinical use.
doi:10.1093/bja/aev229
PMCID: PMC4500763  PMID: 26170348
cell-based therapy; stem cells; traumatic brain injury
18.  Preoperative heart rate and myocardial injury after non-cardiac surgery: results of a predefined secondary analysis of the VISION study 
BJA: British Journal of Anaesthesia  2016;117(2):172-181.
Background
Increased baseline heart rate is associated with cardiovascular risk and all-cause mortality in the general population. We hypothesized that elevated preoperative heart rate increases the risk of myocardial injury after non-cardiac surgery (MINS).
Methods
We performed a secondary analysis of a prospective international cohort study of patients aged ≥45 yr undergoing non-cardiac surgery. Preoperative heart rate was defined as the last measurement before induction of anaesthesia. The sample was divided into deciles by heart rate. Multivariable logistic regression models were used to determine relationships between preoperative heart rate and MINS (determined by serum troponin concentration), myocardial infarction (MI), and death within 30 days of surgery. Separate models were used to test the relationship between these outcomes and predefined binary heart rate thresholds.
Results
Patients with missing outcomes or heart rate data were excluded from respective analyses. Of 15 087 patients, 1197 (7.9%) sustained MINS, 454 of 16 007 patients (2.8%) sustained MI, and 315 of 16 037 patients (2.0%) died. The highest heart rate decile (>96 beats min−1) was independently associated with MINS {odds ratio (OR) 1.48 [1.23–1.77]; P<0.01}, MI (OR 1.71 [1.34–2.18]; P<0.01), and mortality (OR 3.16 [2.45–4.07]; P<0.01). The lowest decile (<60 beats min−1) was independently associated with reduced mortality (OR 0.50 [0.29–0.88]; P=0.02), but not MINS or MI. The predefined binary thresholds were also associated with MINS, but more weakly than the highest heart rate decile.
Conclusions
Preoperative heart rate >96 beats min−1 is associated with MINS, MI, and mortality after non-cardiac surgery. This association persists after accounting for potential confounding factors.
Clinical trial registration
NCT00512109.
doi:10.1093/bja/aew182
PMCID: PMC4954612  PMID: 27440628
heart rate; observational study; surgery
20.  Block of postjunctional muscle-type acetylcholine receptors in vivo causes train-of-four fade in mice 
BJA: British Journal of Anaesthesia  2015;115(1):122-127.
Background
Train-of-four (TOF) fade during nerve-mediated muscle contraction is postulated to be attributable to inhibition of prejunctional nicotinic α3β2 acetylcholine receptors (nAChRs), while decrease of twitch tension is attributable to block of postjunctional muscle nAChRs. The validity of these presumptions was tested using specific prejunctional and postjunctional nAChR antagonists, testing the hypothesis that fade is not always a prejunctional phenomenon.
Methods
Pentobarbital anaesthetized mice had TOF fade measured after administration of: either 0.9% saline; the prejunctional α3β2 nAChR antagonist, dihydro-β-erythroidine (DHβE); the postjunctional nAChR antagonists, α-bungarotoxin (α-BTX) or α-conotoxin GI; and a combination of α-BTX and DHβE; or a combination of α-conotoxin GI and DHβE.
Results
Saline caused no neuromuscular changes. Administration of muscle nAChR antagonists, α-BTX or α-conotoxin GI caused significant decrease of twitch tension and TOF fade compared with baseline (P<0.01). DHβE alone caused no change of twitch tension or fade even after 90 min, but its coadministration with α-BTX or α-conotoxin GI significantly accelerated the onset of paralysis and degree of fade compared with α-BTX or α-conotoxin GI alone (P<0.01).
Conclusions
Occupation of postjunctional nAChRs alone by α-BTX or α-conotoxin GI causes fade. As the prejunctional effects of DHβE on fade became manifest only when co-administered with α-BTX or α-conotoxin GI, specific inhibition of prejunctional nAChR alone is not necessary and sufficient to cause fade. Fade observed during repetitive nerve stimulation can be because of block of either postjunctional nAChRs alone, or block of prejunctional and postjunctional nAChRs together.
doi:10.1093/bja/aev037
PMCID: PMC4471818  PMID: 25835024
acetylcholine; neuromuscular monitoring; neuromuscular block; neuromuscular transmission; receptors; nicotinic
21.  Activity-dependent depression of neuronal sodium channels by the general anaesthetic isoflurane 
BJA: British Journal of Anaesthesia  2015;115(1):112-121.
Background
The mechanisms by which volatile anaesthetics such as isoflurane alter neuronal function are poorly understood, in particular their presynaptic mechanisms. Presynaptic voltage-gated sodium channels (Nav) have been implicated as a target for anaesthetic inhibition of neurotransmitter release. We hypothesize that state-dependent interactions of isoflurane with Nav lead to increased inhibition of Na+ current (INa) during periods of high-frequency neuronal activity.
Methods
The electrophysiological effects of isoflurane, at concentrations equivalent to those used clinically, were measured on recombinant brain-type Nav1.2 expressed in ND7/23 neuroblastoma cells and on endogenous Nav in isolated rat neurohypophysial nerve terminals. Rate constants determined from experiments on the recombinant channel were used in a simple model of Nav gating.
Results
At resting membrane potentials, isoflurane depressed peak INa and shifted steady-state inactivation in a hyperpolarizing direction. After membrane depolarization, isoflurane accelerated entry (τcontrol=0.36 [0.03] ms compared with τisoflurane=0.33 [0.05] ms, P<0.05) and slowed recovery (τcontrol=6.9 [1.1] ms compared with τisoflurane=9.0 [1.9] ms, P<0.005) from apparent fast inactivation, resulting in enhanced depression of INa, during high-frequency stimulation of both recombinant and endogenous nerve terminal Nav. A simple model of Nav gating involving stabilisation of fast inactivation, accounts for this novel form of activity-dependent block.
Conclusions
Isoflurane stabilises the fast-inactivated state of neuronal Nav leading to greater depression of INa during high-frequency stimulation, consistent with enhanced inhibition of fast firing neurones.
doi:10.1093/bja/aev203
PMCID: PMC4471819  PMID: 26089447
anaesthetics, general; isoflurane; presynaptic terminals; voltage-gated sodium channels
22.  Effect of propofol on the medial temporal lobe emotional memory system: a functional magnetic resonance imaging study in human subjects 
BJA: British Journal of Anaesthesia  2015;115(Suppl 1):i104-i113.
Background
Subclinical doses of propofol produce anterograde amnesia, characterized by an early failure of memory consolidation. It is unknown how propofol affects the amygdala-dependent emotional memory system, which modulates consolidation in the hippocampus in response to emotional arousal and neurohumoral stress. We present an event-related functional magnetic resonance imaging study of the effects of propofol on the emotional memory system in human subjects.
Methods
Thirty-five healthy subjects were randomized to receive propofol, at an estimated brain concentration of 0.90 μg ml−1, or placebo. During drug infusion, emotionally arousing and neutral images were presented in a continuous recognition task, while blood-oxygen-level-dependent activation responses were acquired. After a drug-free interval of 2 h, subsequent memory for successfully encoded items was assessed. Imaging analysis was performed using statistical parametric mapping and behavioural analysis using signal detection models.
Results
Propofol had no effect on the stereotypical amygdalar response to emotional arousal, but caused marked suppression of the hippocampal response. Propofol caused memory performance to become uncoupled from amygdalar activation, but it remained correlated with activation in the posterior hippocampus, which decreased in proportion to amnesia.
Conclusions
Propofol is relatively ineffective at suppressing amygdalar activation at sedative doses, but abolishes emotional modulation and causes amnesia via mechanisms that commonly involve hyporesponsiveness of the hippocampus. These findings raise the possibility that amygdala-dependent fear systems may remain intact even when a patient has diminished memory of events. This may be of clinical importance in the perioperative development of fear-based psychopathologies, such as post-traumatic stress disorder.
Clinical trial registration
NCT00504894.
doi:10.1093/bja/aev038
PMCID: PMC4501915  PMID: 26174294
amnesia, chemically induced; amygdala; fMRI; hippocampus; memory, drug effects; propofol, pharmacology
23.  Ageing delays emergence from general anaesthesia in rats by increasing anaesthetic sensitivity in the brain† 
BJA: British Journal of Anaesthesia  2015;115(Suppl 1):i58-i65.
Background
Little is known about ageing-related changes in the brain that affect emergence from general anaesthesia. We used young adult and aged Fischer 344 rats to test the hypothesis that ageing delays emergence from general anaesthesia by increasing anaesthetic sensitivity in the brain.
Methods
Time to emergence was determined for isoflurane (1.5 vol% for 45 min) and propofol (8 mg kg−1 i.v.). The dose of isoflurane required to maintain loss of righting (LOR) was established in young adult and aged rats. The efficacy of methylphenidate to reverse LOR from general anaesthesia was tested. Separate young adult and aged rats with implanted electroencephalogram (EEG) electrodes were used to test whether ageing increases sensitivity to anaesthetic-induced burst suppression.
Results
Mean time to emergence from isoflurane anaesthesia was 47 s [95% CI 33, 60; young adult) compared with 243 s (95% CI 185, 308; aged). For propofol, mean time to emergence was 13.1 min (95% CI 11.9, 14.0; young adult) compared with 23.1 min (95% CI 18.8, 27.9; aged). These differences were statistically significant. When methylphenidate was administered after propofol, the mean time to emergence decreased to 6.6 min (95% CI 5.9, 7.1; young adult) and 10.2 min (95% CI 7.9, 12.3; aged). These reductions were statistically significant. Methylphenidate restored righting in all rats during continuous isoflurane anaesthesia. Aged rats had lower EEG power and were more sensitive to anaesthetic-induced burst suppression.
Conclusions
Ageing delays emergence from general anaesthesia. This is due, at least in part, to increased anaesthetic sensitivity in the brain. Further studies are warranted to establish the underlying causes.
doi:10.1093/bja/aev112
PMCID: PMC4501916  PMID: 26174302
ageing; delayed emergence from anaesthesia; electroencephalography
24.  Age-dependency of sevoflurane-induced electroencephalogram dynamics in children 
BJA: British Journal of Anaesthesia  2015;115(Suppl 1):i66-i76.
Background
General anaesthesia induces highly structured oscillations in the electroencephalogram (EEG) in adults, but the anaesthesia-induced EEG in paediatric patients is less understood. Neural circuits undergo structural and functional transformations during development that might be reflected in anaesthesia-induced EEG oscillations. We therefore investigated age-related changes in the EEG during sevoflurane general anaesthesia in paediatric patients.
Methods
We analysed the EEG recorded during routine care of patients between 0 and 28 yr of age (n=54), using power spectral and coherence methods. The power spectrum quantifies the energy in the EEG at each frequency, while the coherence measures the frequency-dependent correlation or synchronization between EEG signals at different scalp locations. We characterized the EEG as a function of age and within 5 age groups: <1 yr old (n=4), 1–6 yr old (n=12), >6–14 yr old (n=14), >14–21 yr old (n=11), >21–28 yr old (n=13).
Results
EEG power significantly increased from infancy through ∼6 yr, subsequently declining to a plateau at approximately 21 yr. Alpha (8–13 Hz) coherence, a prominent EEG feature associated with sevoflurane-induced unconsciousness in adults, is absent in patients <1 yr.
Conclusions
Sevoflurane-induced EEG dynamics in children vary significantly as a function of age. These age-related dynamics likely reflect ongoing development within brain circuits that are modulated by sevoflurane. These readily observed paediatric-specific EEG signatures could be used to improve brain state monitoring in children receiving general anaesthesia.
doi:10.1093/bja/aev114
PMCID: PMC4501917  PMID: 26174303
electroencephalography; pediatric; sevoflurane
25.  The Ageing Brain: Age-dependent changes in the electroencephalogram during propofol and sevoflurane general anaesthesia 
BJA: British Journal of Anaesthesia  2015;115(Suppl 1):i46-i57.
Background
Anaesthetic drugs act at sites within the brain that undergo profound changes during typical ageing. We postulated that anaesthesia-induced brain dynamics observed in the EEG change with age.
Methods
We analysed the EEG in 155 patients aged 18–90 yr who received propofol (n=60) or sevoflurane (n=95) as the primary anaesthetic. The EEG spectrum and coherence were estimated throughout a 2 min period of stable anaesthetic maintenance. Age-related effects were characterized by analysing power and coherence as a function of age using linear regression and by comparing the power spectrum and coherence in young (18- to 38-yr-old) and elderly (70- to 90-yr-old) patients.
Results
Power across all frequency bands decreased significantly with age for both propofol and sevoflurane; elderly patients showed EEG oscillations ∼2- to 3-fold smaller in amplitude than younger adults. The qualitative form of the EEG appeared similar regardless of age, showing prominent alpha (8–12 Hz) and slow (0.1–1 Hz) oscillations. However, alpha band dynamics showed specific age-related changes. In elderly compared with young patients, alpha power decreased more than slow power, and alpha coherence and peak frequency were significantly lower. Older patients were more likely to experience burst suppression.
Conclusions
These profound age-related changes in the EEG are consistent with known neurobiological and neuroanatomical changes that occur during typical ageing. Commercial EEG-based depth-of-anaesthesia indices do not account for age and are therefore likely to be inaccurate in elderly patients. In contrast, monitoring the unprocessed EEG and its spectrogram can account for age and individual patient characteristics.
doi:10.1093/bja/aev213
PMCID: PMC4501918  PMID: 26174300
ageing; brain monitoring; EEG; elderly; electroencephalography; propofol; sevoflurane

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