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1.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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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