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26.  Perioperative visual loss: what do we know, what can we do? 
BJA: British Journal of Anaesthesia  2009;103(Suppl 1):i31-i40.
Perioperative visual loss (POVL), a rare, but devastating complication, can follow non-ocular surgery. Highest rates of visual loss are with cardiac and spine surgery. The main causes of visual loss after non-ocular surgery are retinal vascular occlusion and ischaemic optic neuropathy. This review updates readers on the incidence, suspected risk factors, diagnosis, and treatment of POVL due to these conditions.
doi:10.1093/bja/aep295
PMCID: PMC2791856  PMID: 20007988
complications, neurological; complications, neuropathy; eye, intraocular pressure; eye, pupil; surgery, spinal
27.  Prothrombin complex concentrate mitigates diffuse bleeding after cardiopulmonary bypass in a porcine model 
BJA: British Journal of Anaesthesia  2010;105(5):576-582.
Background
Extracorporeal circuit priming and intravascular volume expansion during cardiopulmonary bypass (CPB) may lead to dilutional coagulopathy and excessive diffuse postoperative bleeding. Prothrombin complex concentrate (PCC) containing clotting factors II (FII), VII (FVII), IX (FIX), and X (FX) could be of potential value in correcting dilutional coagulopathy and reducing blood loss.
Methods
Anaesthetized pigs underwent CPB with hypothermia for 2 h at 25°C followed by 1 h of normothermia. Approximately 1 h after CPB, animals randomly received either isotonic saline 1 ml kg−1 or PCC 30 IU kg−1 in a volume of 1 ml kg−1. Diffuse coagulopathic bleeding was assessed as suture hole blood loss from a Gore-Tex patch placed over a full-thickness incision in the left carotid artery.
Results
After CPB, levels of FII, FVII, FIX, and FX declined from baseline by 32% to 48%, and PCC fully or partially reversed those deficits. Median suture hole blood loss after administration of saline placebo was 74 ml. PCC reduced suture hole bleeding by a median of 54 ml with a 95% confidence interval of 6–112 ml (P=0.026) compared with saline. PCC, but not saline, normalized skin bleeding time. Peak thrombin generation markedly decreased after CPB, but then returned in PCC-treated animals to a level higher than baseline by 28.7 nM (14.5–41.1 nM; P=0.031).
Conclusions
PCC was effective in correcting dilutional coagulopathy and reducing diffuse bleeding in an in vivo large-animal CPB model. Further research is warranted on PCC as a haemostatic agent in CPB.
doi:10.1093/bja/aeq216
PMCID: PMC2955534  PMID: 20716565
blood coagulation disorders; cardiopulmonary bypass; haemodilution; haemorrhage; prothrombin complex concentrates
28.  Mechanical and cold hypersensitivity in nerve-injured C57BL/6J mice is not associated with fear-avoidance- and depression-related behaviour 
British journal of anaesthesia  2007;98(6):816-822.
Background
Neuropathic pain is associated with significant co-morbidity, including anxiety and depression, which impact considerably on the overall patient experience. However, pain co-morbidity symptoms are rarely assessed in animal models of neuropathic pain. To improve the clinical validity of a widely used rodent model of traumatic peripheral neuropathy, we have investigated fear-avoidance- and depression-related behaviours in nerve-injured and sham-operated mice over a 4 week period.
Methods
Male C57BL/6J mice were subjected to partial sciatic nerve ligation (PSNL) or sham surgery and were assessed on days 7, 14, and 28 after operation. Withdrawal thresholds to punctate mechanical and cooling stimuli were measured. Mice were tested on the novel open-field and elevated plus-maze tests for fear-avoidance behaviour, and on the tail suspension test for depression-related behaviour.
Results
Hypersensitivity to punctate mechanical and cool stimuli was evident up to day 28 after PSNL. However, there was no change in fear-avoidance- or depression-related behaviours regardless of interval after-surgery.
Conclusion
These data demonstrate that pain behaviour in nerve-injured C57BL/6J mice was not associated with alterations in emotion-related behaviours.
doi:10.1093/bja/aem087
PMCID: PMC2656645  PMID: 17478455
mouse; pain, chronic; pain, neuropathic; pain, psychological variables; research, animal
29.  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
30.  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
31.  What comes first? The dynamics of cerebral oxygenation and blood flow in response to changes in arterial pressure and intracranial pressure after head injury 
Background
Brain tissue partial oxygen pressure (PbtO2) and near-infrared spectroscopy (NIRS) are novel methods to evaluate cerebral oxygenation. We studied the response patterns of PbtO2, NIRS, and cerebral blood flow velocity (CBFV) to changes in arterial pressure (AP) and intracranial pressure (ICP).
Methods
Digital recordings of multimodal brain monitoring from 42 head-injured patients were retrospectively analysed. Response latencies and patterns of PbtO2, NIRS-derived parameters [tissue oxygenation index (TOI) and total haemoglobin index (THI)], and CBFV reactions to fluctuations of AP and ICP were studied.
Results
One hundred and twenty-one events were identified. In reaction to alterations of AP, ICP reacted first [4.3 s; inter-quartile range (IQR) −4.9 to 22.0 s, followed by NIRS-derived parameters and CBFV (10.9 s; IQR: −5.9 to 39.6 s, 12.1 s; IQR: −3.0 to 49.1 s, 14.7 s; IQR: −8.8 to 52.3 s for THI, CBFV, and TOI, respectively), with PbtO2 reacting last (39.6 s; IQR: 16.4 to 66.0 s). The differences in reaction time between NIRS parameters and PbtO2 were significant (P<0.001). Similarly when reactions to ICP changes were analysed, NIRS parameters preceded PbtO2 (7.1 s; IQR: −8.8 to 195.0 s, 18.1 s; IQR: −20.6 to 80.7 s, 22.9 s; IQR: 11.0 to 53.0 s for THI, TOI, and PbtO2, respectively). Two main patterns of responses to AP changes were identified. With preserved cerebrovascular reactivity, TOI and PbtO2 followed the direction of AP. With impaired cerebrovascular reactivity, TOI and PbtO2 decreased while AP and ICP increased. In 77% of events, the direction of TOI changes was concordant with PbtO2.
Conclusions
NIRS and transcranial Doppler signals reacted first to AP and ICP changes. The reaction of PbtO2 is delayed. The results imply that the analysed modalities monitor different stages of cerebral oxygenation.
doi:10.1093/bja/aer324
PMCID: PMC3236021  PMID: 22037222
brain tissue partial oxygen pressure; cerebral haemodynamics; cerebral oxygenation; cerebrovascular reactivity; near-infrared spectroscopy; tissue haemoglobin index; tissue oxygenation index
33.  Effect of age on intraoperative cerebrovascular autoregulation and near-infrared spectroscopy-derived cerebral oxygenation 
BJA: British Journal of Anaesthesia  2011;107(5):742-748.
Background
Age is an important risk factor for perioperative cerebral complications such as stroke, postoperative cognitive dysfunction, and delirium. We explored the hypothesis that intraoperative cerebrovascular autoregulation is less efficient and brain tissue oxygenation lower in elderly patients, thus, increasing the vulnerability of elderly brains to systemic insults such as hypotension.
Methods
We monitored intraoperative cerebral perfusion in 50 patients aged 18–40 and 77 patients >65 yr at two Swiss university hospitals. Mean arterial pressure (MAP) was measured continuously using a plethysmographic method. An index of cerebrovascular autoregulation (Mx) was calculated based on changes in transcranial Doppler flow velocity due to changes in MAP. Cerebral oxygenation was assessed by the tissue oxygenation index (TOI) using near-infrared spectroscopy. End-tidal CO2, O2, and sevoflurane concentrations and peripheral oxygen saturation were recorded continuously. Standardized anaesthesia was administered in all patients (thiopental, sevoflurane, fentanyl, atracurium).
Results
Autoregulation was less efficient in patients aged >65 yr [by 0.10 (se 0.04; P=0.020)] in a multivariable linear regression analysis. This difference was not attributable to differences in MAP, end-tidal CO2, or higher doses of sevoflurane. TOI was not significantly associated with age, sevoflurane dose, or Mx but increased with increasing flow velocity [by 0.09 (se 0.04; P=0.028)] and increasing MAP [by 0.11 (se 0.05; P=0.043)].
Conclusions
Our results do not support the hypothesis that older patients' brains are more vulnerable to systemic insults. The difference of autoregulation between the two groups was small and most likely clinically insignificant.
doi:10.1093/bja/aer252
PMCID: PMC3192482  PMID: 21835838
age groups; anaesthesia; cerebrovascular circulation
34.  General anaesthesia is associated with increased risk of surgical site infection after Caesarean delivery compared with neuraxial anaesthesia: a population-based study 
BJA: British Journal of Anaesthesia  2011;107(5):757-761.
Background
This study compared the odds ratio (OR) of surgical site infection (SSI) within 30 days after operation with general anaesthesia (GA) or neuraxial anaesthesia (NA) in Taiwanese women undergoing Caesarean delivery (CD).
Methods
An epidemiologic design was used. The study population was based on the records of all deliveries in hospitals or obstetric clinics between January 2002 and December 2006 in Taiwan. Anonymized claim data from the Taiwan National Health Insurance Research Database (NHIRD) were analysed. Women who received CD were identified from the NHIRD by Diagnosis-Related Group codes. The mode of anaesthesia was defined by order codes. Multivariate logistic regression was used to estimate the OR and associated 95% confidence interval (CI) of post-CD SSIs for GA when compared with NA. The outcome was whether a woman had been diagnosed as having an SSI during the hospitalization or was re-hospitalized within 30 days after CD for the treatment of SSIs using five or 81 International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes.
Results
Among the 303 834 Taiwanese women who underwent CD during the 5 yr observation period, the 30 day post-CD SSI rate was 0.3% or 0.9% based on five or 81 ICD-9-CM codes. The multivariate-adjusted OR of having post-CD SSIs in the GA group was 3.73 (95% CI, 3.07–4.53) compared with the NA group (P<0.001) using five ICD-9-CM codes for the definition of SSI.
Conclusions
GA for CD was associated with a higher risk of SSI when compared with neuraxial anaesthesia.
doi:10.1093/bja/aer262
PMCID: PMC3243922  PMID: 21857016
anaesthesia; Caesarean section; general anaesthesia; neuraxial anaesthesia; surgical site infection
35.  Effect of phenylephrine and ephedrine bolus treatment on cerebral oxygenation in anaesthetized patients 
BJA: British Journal of Anaesthesia  2011;107(2):209-217.
Background
How phenylephrine and ephedrine treatments affect global and regional haemodynamics is of major clinical relevance. Cerebral tissue oxygen saturation ()-guided management may improve postoperative outcome. The physiological variables responsible for changes induced by phenylephrine and ephedrine bolus treatment in anaesthetized patients need to be defined.
Methods
A randomized two-treatment cross-over trial was conducted: one bolus dose of phenylephrine (100–200 µg) and one bolus dose of ephedrine (5–20 mg) were given to 29 ASA I–III patients anaesthetized with propofol and remifentanil. , mean arterial pressure (MAP), cardiac output (CO), and other physiological variables were recorded before and after treatments. The associations of changes were analysed using linear-mixed models.
Results
The CO decreased significantly after phenylephrine treatment [▵CO=−2.1 (1.4) litre min−1, P<0.001], but was preserved after ephedrine treatment [▵CO=0.5 (1.4) litre min−1, P>0.05]. The was significantly decreased after phenylephrine treatment [▵=−3.2 (3.0)%, P<0.01] but preserved after ephedrine treatment [▵=0.04 (1.9)%, P>0.05]. CO was identified to have the most significant association with (P<0.001). After taking CO into consideration, the other physiological variables, including MAP, were not significantly associated with (P>0.05).
Conclusions
Associated with changes in CO, decreased after phenylephrine treatment, but remained unchanged after ephedrine treatment. The significant correlation between CO and implies a cause–effect relationship between global and regional haemodynamics.
doi:10.1093/bja/aer150
PMCID: PMC3136202  PMID: 21642644
cardiac output; cerebral tissue oxygen saturation; ephedrine; mean arterial pressure; phenylephrine
36.  Are anaesthetics toxic to the brain? 
It has been assumed that anaesthetics have minimal or no persistent effects after emergence from anaesthesia. However, general anaesthetics act on multiple ion channels, receptors, and cell signalling systems in the central nervous system to produce anaesthesia, so it should come as no surprise that they also have non-anaesthetic actions that range from beneficial to detrimental. Accumulating evidence is forcing the anaesthesia community to question the safety of general anaesthesia at the extremes of age. Preclinical data suggest that inhaled anaesthetics can have profound and long-lasting effects during key neurodevelopmental periods in neonatal animals by increasing neuronal cell death (apoptosis) and reducing neurogenesis. Clinical data remain conflicting on the significance of these laboratory data to the paediatric population. At the opposite extreme in age, elderly patients are recognized to be at an increased risk of postoperative cognitive dysfunction (POCD) with a well-recognized decline in cognitive function after surgery. The underlying mechanisms and the contribution of anaesthesia in particular to POCD remain unclear. Laboratory models suggest anaesthetic interactions with neurodegenerative mechanisms, such as those linked to the onset and progression of Alzheimer's disease, but their clinical relevance remains inconclusive. Prospective randomized clinical trials are underway to address the clinical significance of these findings, but there are major challenges in designing, executing, and interpreting such trials. It is unlikely that definitive clinical studies absolving general anaesthetics of neurotoxicity will become available in the near future, requiring clinicians to use careful judgement when using these profound neurodepressants in vulnerable patients.
doi:10.1093/bja/aer122
PMCID: PMC3159425  PMID: 21616941
anaesthesia, general; Alzheimer's disease; neurobehavioural manifestations; postoperative complications
37.  Analysing a family-centred preoperative intervention programme: a dismantling approach 
BJA: British Journal of Anaesthesia  2011;106(5):713-718.
Background
The goal of this project was to identify key effective components of ADVANCE, a family-centred preoperative intervention programme, through the use of a dismantling approach. ADVANCE was previously demonstrated to be more effective than parental presence and just as effective as midazolam in reducing children's preoperative anxiety. The total programme, however, may be difficult to implement in hospitals across the country.
Methods
Subjects in this follow-up dismantling report were 96 children aged 2–10 who were part of the original study and who underwent anaesthesia and surgery. Baseline characteristics, parental adherence to the components of ADVANCE, and child and parent anxiety were assessed.
Results
We found that greater parental adherence to the ADVANCE intervention was associated with lower child anxiety before surgery. The two components of ADVANCE that emerged as having a significant impact on children's anxiety were practising with the anaesthesia mask at home and parental planning and use of distraction in the preoperative holding area. In fact, not only did children experience significantly less preoperative anxiety when their parents were adherent to mask practise and use of distraction, their anxiety tended to remain stable and relatively low throughout the preoperative period.
Conclusions
Shaping and exposure (i.e. practise with the anaesthesia mask) and parental use of distraction in the surgical setting are two beneficial components that could be included in preoperative preparation programmes that will be designed in the future.
doi:10.1093/bja/aer010
PMCID: PMC3077749  PMID: 21324929
children; surgery, paediatric; surgery, preoperative period
38.  Neuromuscular pharmacodynamics of mivacurium in adults with major burns 
BJA: British Journal of Anaesthesia  2011;106(5):675-679.
Background
Mivacurium is metabolized by plasma pseudocholinesterase (PChE) enzyme, which is decreased in burns. We tested whether the decreased metabolism of mivacurium due to decreased PChE activity can overcome the pharmacodynamic resistance to non-depolarizing relaxants previously seen in major burns.
Methods
Thirty adults with 35 (13)% [mean (sd)] burn were studied at 5–91 post-burn days and 31 non-burns matched controls. Mivacurium 0.2 mg kg−1 was administered as a single bolus. Neuromuscular block was monitored with single-twitch response using TOF-Watch™. Onset time (drug administration to maximal twitch suppression) and spontaneous recovery were measured.
Results
Onset time was significantly prolonged in burns when compared with non-burns (115 vs 90 s; P<0.001). The PChE levels were lower in burns [1432 (916) vs 2866 (731) IU litre−1; P<0.001] and the neuromuscular recovery to 50% of baseline twitch height was prolonged in burns (41 vs 26 min; P<0.001). There was a significant correlation between PChE and time to 50% recovery for the whole group together (r=−0.6; P<0.001). The dibucaine numbers were not different.
Conclusions
The prolonged onset time suggests resistance to neuromuscular effects, whereas the prolonged recovery suggests increased sensitivity. This divergent response can be explained by qualitative and quantitative changes in acetylcholine receptor expression causing resistance and decreased PChE activity causing sensitivity. Despite using a relatively large dose of mivacurium (0.2 mg kg−1) in the presence of decreased PChE levels, this did not overcome the resistance resulting from up-regulated receptors.
doi:10.1093/bja/aer023
PMCID: PMC3077750  PMID: 21354998
neuromuscular relaxants, mivacurium; pharmacodynamics; trauma, burns
39.  Monitoring non-invasive cardiac output and stroke volume during experimental human hypovolaemia and resuscitation 
Background
Multiple methods for non-invasive measurement of cardiac output (CO) and stroke volume (SV) exist. Their comparative capabilities are not clearly established.
Methods
Healthy human subjects (n=21) underwent central hypovolaemia through progressive lower body negative pressure (LBNP) until the onset of presyncope, followed by termination of LBNP, to simulate complete resuscitation. Measurement methods were electrical bioimpedance (EBI) of the thorax and three measurements of CO and SV derived from the arterial blood pressure (ABP) waveform: the Modelflow (MF) method, the long-time interval (LTI) method, and pulse pressure (PP). We computed areas under receiver-operating characteristic curves (ROC AUCs) for the investigational metrics, to determine how well they discriminated between every combination of LBNP levels.
Results
LTI and EBI yielded similar reductions in SV during progressive hypovolaemia and resuscitation (correlation coefficient 0.83) with ROC AUCs for distinguishing major LBNP (−60 mm Hg) vs resuscitation (0 mm Hg) of 0.98 and 0.99, respectively. MF yielded very similar reductions and ROC AUCs during progressive hypovolaemia, but after resuscitation, MF-CO did not return to baseline, yielding lower ROC AUCs (ΔROC AUC range, −0.18 to −0.26, P<0.01). PP declined during hypovolaemia but tended to be an inferior indicator of specific LBNP levels, and PP did not recover during resuscitation, yielding lower ROC curves (P<0.01).
Conclusions
LTI, EBI, and MF were able to track progressive hypovolaemia. PP decreased during hypovolaemia but its magnitude of reduction underestimated reductions in SV. PP and MF were inferior for the identification of resuscitation.
doi:10.1093/bja/aeq295
PMCID: PMC3000628  PMID: 21051492
arterial pressure, measurement; blood, loss; cardiovascular system, responses; equipment, finapres; monitoring, cardiopulmonary
40.  Revised cardiac risk index and postoperative morbidity after elective orthopaedic surgery: a prospective cohort study 
BJA: British Journal of Anaesthesia  2010;105(6):744-752.
Background
The revised cardiac risk index (RCRI) is associated strongly with increased cardiac ischaemic risk and perioperative death. Associations with non-cardiac morbidity in non-cardiac surgery have not been explored. In the elective orthopaedic surgical population, morbidity is common but preoperative predictors are unclear. We hypothesized that RCRI would identify individuals at increased risk of non-cardiac morbidity in this surgically homogenous population.
Methods
Five hundred and sixty patients undergoing elective primary (>90%) and revision hip and knee procedures were studied. A modified RCRI (mRCRI) score was calculated, weighting intermediate and low risk factors. The primary endpoint was the development of morbidity, collected prospectively using the Postoperative Morbidity Survey, on postoperative day (POD) 5.
Results
Morbidity on POD 5 was more frequent in patients with mRCRI ≥3 {relative risk 1.7, [95% confidence interval (CI): 1.4–2.1]; P<0.001}. Time to hospital discharge was delayed in patients with mRCRI score ≥3 (log-rank test, P=0.0002). Pulmonary (P<0.001), infectious (P=0.001), cardiovascular (P=0.0003), renal (P<0.0001), wound (P=0.02), and neurological (P=0.002) morbidities were more common in patients with mRCRI score ≥3. Pre/postoperative haematocrit, anaesthetic/analgesic technique, and postoperative temperature were similar across mRCRI groups. There were significant associations with hospital stay, as measured by the area under the receiver-operating characteristic curves for mRCRI 0.64 (95% CI: 0.58–0.70) and POSSUM 0.70 (95% CI: 0.63–0.75).
Conclusions
mRCRI score ≥3 is associated with increased postoperative non-cardiac morbidity and prolonged hospital stay after elective orthopaedic procedures. mRCRI can contribute to objective risk stratification of postoperative morbidity.
doi:10.1093/bja/aeq245
PMCID: PMC2982697  PMID: 20876700
assessment, preanaesthetic; complications, morbidity; surgery, non-cardiac; surgery, orthopaedic
41.  Incidence and risk factors for fatal pulmonary embolism after major trauma: a nested cohort study† 
BJA: British Journal of Anaesthesia  2010;105(5):596-602.
Background
Venous thromboembolism is common after major trauma. Strategies to prevent fatal pulmonary embolism (PE) are widely utilized, but the incidence and risk factors for fatal PE are poorly understood.
Methods
Using linked data from the intensive care unit, trauma registry, Western Australian Death Registry, and post-mortem reports, the incidence and risk factors for fatal PE in a consecutive cohort of major trauma patients, admitted between 1994 and 2002, were assessed. Non-linear relationships between continuous predictors and risk of fatal PE were modelled by logistic regression.
Results
Of the 971 consecutive trauma patients considered in the study, 134 (13.8%) died after their injuries. Fatal PE accounted for 11.9% of all deaths despite unfractionated heparin prophylaxis being used in 44% of these patients. Fatal PE occurred in those who were older (mean age 51- vs 37-yr-old, P=0.01), with more co-morbidities (Charlson's co-morbidity index 1.1 vs 0.2, P=0.01), had a larger BMI (31.8 vs 24.5, P=0.01), and less severe head and systemic injuries when compared with those who died of other causes. Sites of injuries were not significantly related to the risk of fatal PE. Fatal PE occurred much later than deaths from other causes (median 18 vs 2 days, P=0.01), and the estimated attributable mortality of PE was 49% (95% confidence interval 36–62%).
Conclusions
Fatal PE appeared to be a potential preventable cause of late mortality after major trauma. Severity of injuries, co-morbidity, and BMI were important risk factors for fatal PE after major trauma.
doi:10.1093/bja/aeq254
PMCID: PMC2955535  PMID: 20861095
mortality; prevention; thromboembolism; traumatic injuries
42.  Sugammadex compared with neostigmine/glycopyrrolate for routine reversal of neuromuscular block: a systematic review and economic evaluation† 
BJA: British Journal of Anaesthesia  2010;105(5):558-567.
Summary
The cost-effectiveness of sugammadex for the routine reversal of muscle relaxation produced by rocuronium or vecuronium in UK practice is uncertain. We performed a systematic review of randomized controlled trials of sugammadex compared with neostigmine/glycopyrrolate and an economic assessment of sugammadex for the reversal of moderate or profound neuromuscular block (NMB) produced by rocuronium or vecuronium. The economic assessment aimed to establish the reduction in recovery time and the ‘value of time saved’ which would be necessary for sugammadex to be potentially cost-effective compared with existing practice. Three trials indicated that sugammadex 2 mg kg−1 (4 mg kg−1) produces more rapid recovery from moderate (profound) NMB than neostigmine/glycopyrrolate. The economic assessment indicated that if the reductions in recovery time associated with sugammadex in the trials are replicated in routine practice, sugammadex would be cost-effective if those reductions are achieved in the operating theatre (assumed value of staff time, £4.44 per minute), but not if they are achieved in the recovery room (assumed value of staff time, £0.33 per minute). However, there is considerable uncertainty in these results. Sugammadex has the potential to be cost-effective compared with neostigmine/glycopyrrolate for the reversal of rocuronium-induced moderate or profound NMB, provided that the time savings observed in trials can be achieved and put to productive use in clinical practice. Further research is required to evaluate the effects of sugammadex on patient safety, predictability of recovery from NMB, patient outcomes, and efficient use of resources.
doi:10.1093/bja/aeq269
PMCID: PMC2955536  PMID: 20935005
clinical trials; neuromuscular block, recovery; neuromuscular block, rocuronium
43.  Sugammadex for reversal of neuromuscular block after rapid sequence intubation: a systematic review and economic assessment† 
BJA: British Journal of Anaesthesia  2010;105(5):568-575.
Summary
Sugammadex 16 mg kg−1 can be used for the immediate reversal of neuromuscular block 3 min after administration of rocuronium and could be used in place of succinylcholine for emergency intubation. We have systematically reviewed the efficacy and cost-effectiveness and made an economic assessment of sugammadex for immediate reversal. The economic assessment investigated whether sugammadex appears cost-effective under various assumptions about the value of any reduction in recovery time with sugammadex, the likelihood of a ‘can't intubate, can't ventilate’ (CICV) event, the age of the patient, and the length of the procedure. Three trials were included in the efficacy review. Sugammadex administered 3 or 5 min after rocuronium produced markedly faster recovery than placebo or spontaneous recovery from succinylcholine-induced block. No published economic evaluations were found. Our economic analyses showed that sugammadex appears more cost-effective, where the value of any reduction in recovery time is greater, where the reduction in mortality compared with succinylcholine is greater, and where the patient is younger, for lower probabilities of a CICV event and for long procedures which do not require profound block throughout. Because of the lack of evidence, the value of some parameters remains unknown, which makes it difficult to provide a definitive assessment of the cost-effectiveness of sugammadex in practice. The use of sugammadex in combination with high-dose rocuronium is efficacious. Further research is needed to clarify key parameters in the analysis and to allow a fuller economic assessment.
doi:10.1093/bja/aeq270
PMCID: PMC2955537  PMID: 20937718
complications, intubation tracheal; neuromuscular block, recovery; neuromuscular block, rocuronium; neuromuscular block, succinylcholine
45.  Topical capsaicin for pain management: therapeutic potential and mechanisms of action of the new high-concentration capsaicin 8% patch 
BJA: British Journal of Anaesthesia  2011;107(4):490-502.
Summary
Topical capsaicin formulations are used for pain management. Safety and modest efficacy of low-concentration capsaicin formulations, which require repeated daily self-administration, are supported by meta-analyses of numerous studies. A high-concentration capsaicin 8% patch (Qutenza™) was recently approved in the EU and USA. A single 60-min application in patients with neuropathic pain produced effective pain relief for up to 12 weeks. Advantages of the high-concentration capsaicin patch include longer duration of effect, patient compliance, and low risk for systemic effects or drug–drug interactions. The mechanism of action of topical capsaicin has been ascribed to depletion of substance P. However, experimental and clinical studies show that depletion of substance P from nociceptors is only a correlate of capsaicin treatment and has little, if any, causative role in pain relief. Rather, topical capsaicin acts in the skin to attenuate cutaneous hypersensitivity and reduce pain by a process best described as ‘defunctionalization’ of nociceptor fibres. Defunctionalization is due to a number of effects that include temporary loss of membrane potential, inability to transport neurotrophic factors leading to altered phenotype, and reversible retraction of epidermal and dermal nerve fibre terminals. Peripheral neuropathic hypersensitivity is mediated by diverse mechanisms, including altered expression of the capsaicin receptor TRPV1 or other key ion channels in affected or intact adjacent peripheral nociceptive nerve fibres, aberrant re-innervation, and collateral sprouting, all of which are defunctionalized by topical capsaicin. Evidence suggests that the utility of topical capsaicin may extend beyond painful peripheral neuropathies.
doi:10.1093/bja/aer260
PMCID: PMC3169333  PMID: 21852280
capsaicin; nerve growth factor; neuropathic pain; nociceptor; TRPV1
46.  Antinociceptive and anti-inflammatory effects of choline in a mouse model of postoperative pain 
BJA: British Journal of Anaesthesia  2010;105(2):201-207.
Background
Choline is a dietary supplement that activates α7 nicotinic receptors. α7 nicotinic activation reduces cytokine production by macrophages and has antinociceptive activity in inflammatory pain models. We hypothesized that systemic administration of choline would reduce the inflammatory response from macrophages and have antinociceptive efficacy in a murine model of postoperative pain.
Methods
We studied the response of wild-type and α7 nicotinic knockout mice to heat and punctate pressure after a model surgical procedure. We investigated the effect of genotype and choline treatment on α-bungarotoxin binding to, and their production of tumour necrosis factor (TNF) from, macrophages.
Results
Choline provided moderate antinociception. The ED50 for choline inhibition of heat-induced allodynia was 1.7 mg kg−1 h−1. The ED50 for punctate pressure threshold was 4.7 mg kg−1 h−1 choline. α7 nicotinic knockout mice had no change in hypersensitivity to heat or pressure and were significantly different from littermate controls when treated with choline 5 mg kg−1 h−1 (P<0.05, 0.01). Choline 100 mM reduced binding of α-bungarotoxin to macrophages by 72% and decreased their release of TNF by up to 51 (sd 11)%. There was no difference by genotype in the inhibition of TNF release by choline.
Conclusions
Systemic choline is a moderately effective analgesic via activation of α7 nicotinic acetylcholine receptors. The antinocicepive effect may not be mediated by a reduction of TNF pathway cytokine release from macrophages. Although choline at millimolar concentrations clearly inhibits the release of TNF, this effect is not α7 subunit-dependent and occurs at concentrations likely higher than reached systemically in vivo.
doi:10.1093/bja/aeq113
PMCID: PMC2903311  PMID: 20511332
acetylcholine; acute pain, novel techniques; pharmacodynamics; pharmacology, dose–response; pharmacology, general
47.  Clinically relevant doses of lidocaine and bupivacaine do not impair cutaneous wound healing in mice† 
BJA: British Journal of Anaesthesia  2010;104(6):768-773.
Background
Lidocaine and bupivacaine are commonly infiltrated into surgical cutaneous wounds to provide local anaesthesia after surgical procedures. However, very little is known about their effects on cutaneous wound healing. If an inhibitory effect is demonstrated, then the balance between the benefits of postoperative local anaesthesia and the negatives of impaired cutaneous wound healing may affect the decision to use local anaesthesia or not. Furthermore, if a difference in the rate of healing of lidocaine- and bupivacaine-treated cutaneous wounds is revealed, or if an inhibitory effect is found to be dose-dependent, then this may well influence the choice of agent and its concentration for clinical use.
Methods
Immediately before incisional wounding, we administered lidocaine and bupivacaine intradermally to adult female mice, some of which had been ovariectomized to act as a model of post-menopausal women (like post-menopausal women, ovariectomized mice heal wounds poorly, with increased proteolysis and inflammation). Day 3 wound tissue was analysed histologically and tested for expression of inflammatory and proteolytic factors.
Results
On day 3 post-wounding, wound areas and extent of re-epithelialization were comparable between the control and local anaesthetic-treated animals, in both intact and ovariectomized groups. Both tested drugs significantly increased wound activity of the degradative enzyme matrix metalloproteinase-2 relative to controls, while lidocaine also increased wound neutrophil numbers.
Conclusions
Although lidocaine and bupivacaine influenced local inflammatory and proteolytic factors, they did not impair the rate of healing in either of two well-established models (mimicking normal human wound healing and impaired age-related healing).
doi:10.1093/bja/aeq093
PMCID: PMC2867659  PMID: 20418532
anaesthetics local, bupivacaine; anaesthetics local, lidocaine; mouse
48.  Two cases of variceal haemorrhage during living-donor liver transplantation 
BJA: British Journal of Anaesthesia  2011;106(4):537-539.
Some patients with cirrhosis experience rupture of venous varices before operation, and liver transplantation is a therapy of last resort for these patients. However, we have experienced two cases of intraoperative rupture in whom no abnormalities of the venous varices were seen on endoscopy before operation. One patient with ruptured gastrointestinal varices was treated by direct surgical ligation and the other with ruptured oesophageal gastric varices, spontaneously recovered with a Sengstaken–Blakemore tube. These cases suggest that acute variceal haemorrhage should always be considered as a possibility during living-donor liver transplantation in patients with a history of upper gastrointestinal bleeding. Careful observation of the nasogastic tube is important during clamping of the hepatic portal vein.
doi:10.1093/bja/aer008
PMCID: PMC3060377  PMID: 21324927
living-donor liver transplantation; portal hypertension; variceal haemorrhage
49.  Mathematical model for describing cerebral oxygen desaturation in patients undergoing deep hypothermic circulatory arrest 
Background
Surgical treatment for aortic arch disease requiring periods of circulatory arrest is associated with a spectrum of neurological sequelae. Cerebral oximetry can non-invasively monitor patients for cerebral ischaemia even during periods of circulatory arrest. We hypothesized that cerebral desaturation during circulatory arrest could be described by a mathematical relationship that is time-dependent.
Methods
Cerebral desaturation curves obtained from 36 patients undergoing aortic surgery with deep hypothermic circulatory arrest (DHCA) were used to create a non-linear mixed model. The model assumes that the rate of oxygen decline is greatest at the beginning before steadily transitioning to a constant. Leave-one-out cross-validation and jackknife methods were used to evaluate the validity of the predictive model.
Results
The average rate of cerebral desaturation during DHCA can be described as: Scto2[t]=81.4−(11.53+0.37×t) (1−0.88×exp (−0.17×t)). Higher starting Scto2 values and taller patient height were also associated with a greater decline rate of Scto2. Additionally, a predictive model was derived after the functional form of a×log (b+c×δ), where δ is the degree of Scto2 decline after 15 min of DHCA. The model enables the estimation of a maximal acceptable arrest time before reaching an ischaemic threshold. Validation tests showed that, for the majority, the prediction error is no more than ±3 min.
Conclusions
We were able to create two mathematical models, which can accurately describe the rate of cerebral desaturation during circulatory arrest at 12–15°C as a function of time and predict the length of arrest time until a threshold value is reached.
doi:10.1093/bja/aep335
PMCID: PMC2791548  PMID: 19933513
brain, ischaemia; brain, oxygen consumption; hypothermia
50.  Detection, evaluation, and management of preoperative anaemia in the elective orthopaedic surgical patient: NATA guidelines 
Previously undiagnosed anaemia is common in elective orthopaedic surgical patients and is associated with increased likelihood of blood transfusion and increased perioperative morbidity and mortality. A standardized approach for the detection, evaluation, and management of anaemia in this setting has been identified as an unmet medical need. A multidisciplinary panel of physicians was convened by the Network for Advancement of Transfusion Alternatives (NATA) with the aim of developing practice guidelines for the detection, evaluation, and management of preoperative anaemia in elective orthopaedic surgery. A systematic literature review and critical evaluation of the evidence was performed, and recommendations were formulated according to the method proposed by the Grades of Recommendation Assessment, Development and Evaluation (GRADE) Working Group. We recommend that elective orthopaedic surgical patients have a haemoglobin (Hb) level determination 28 days before the scheduled surgical procedure if possible (Grade 1C). We suggest that the patient's target Hb before elective surgery be within the normal range, according to the World Health Organization criteria (Grade 2C). We recommend further laboratory testing to evaluate anaemia for nutritional deficiencies, chronic renal insufficiency, and/or chronic inflammatory disease (Grade 1C). We recommend that nutritional deficiencies be treated (Grade 1C). We suggest that erythropoiesis-stimulating agents be used for anaemic patients in whom nutritional deficiencies have been ruled out, corrected, or both (Grade 2A). Anaemia should be viewed as a serious and treatable medical condition, rather than simply an abnormal laboratory value. Implementation of anaemia management in the elective orthopaedic surgery setting will improve patient outcomes.
doi:10.1093/bja/aeq361
PMCID: PMC3000629  PMID: 21148637
anaemia; blood transfusion; orthopaedic surgery; preoperative assessment; preoperative preparation

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