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1.  Presynaptic inhibition of the release of multiple major central nervous system neurotransmitter types by the inhaled anaesthetic isoflurane 
BJA: British Journal of Anaesthesia  2012;110(4):592-599.
Presynaptic effects of general anaesthetics are not well characterized. We tested the hypothesis that isoflurane exhibits transmitter-specific effects on neurotransmitter release from neurochemically and functionally distinct isolated mammalian nerve terminals.
Nerve terminals from adult male rat brain were prelabelled with [3H]glutamate and [14C]GABA (cerebral cortex), [3H]norepinephrine (hippocampus), [14C]dopamine (striatum), or [3H]choline (precursor of [3H]acetylcholine; striatum). Release evoked by depolarizing pulses of 4-aminopyridine (4AP) or elevated KCl was quantified using a closed superfusion system.
Isoflurane at clinical concentrations (<0.7 mM; ∼2 times median anaesthetic concentration) inhibited Na+ channel-dependent 4AP-evoked release of the five neurotransmitters tested in a concentration-dependent manner. Isoflurane was a more potent inhibitor [expressed as IC50 (sem)] of glutamate release [0.37 (0.03) mM; P<0.05] compared with the release of GABA [0.52 (0.03) mM], norepinephrine [0.48 (0.03) mM], dopamine [0.48 (0.03) mM], or acetylcholine [0.49 (0.02) mM]. Inhibition of Na+ channel-independent release evoked by elevated K+ was not significant at clinical concentrations of isoflurane, with the exception of dopamine release [IC50=0.59 (0.03) mM].
Isoflurane inhibited the release of the major central nervous system neurotransmitters with selectivity for glutamate release, consistent with both widespread inhibition and nerve terminal-specific presynaptic effects. Glutamate release was most sensitive to inhibition compared with GABA, acetylcholine, dopamine, and norepinephrine release due to presynaptic specializations in ion channel expression, regulation, and/or coupling to exocytosis. Reductions in neurotransmitter release by volatile anaesthetics could contribute to altered synaptic transmission, leading to therapeutic and toxic effects involving all major neurotransmitter systems.
PMCID: PMC3600942  PMID: 23213036
acetylcholine; γ-aminobutyric acid; anaesthetics; dopamine; exocytosis; glutamate; Na+ channels; nerve terminal; neurotransmitter release; norepinephrine
2.  Falls and major orthopaedic surgery with peripheral nerve blockade: a systematic review and meta-analysis 
BJA: British Journal of Anaesthesia  2013;110(4):518-528.
The objective of this systematic review with meta-analysis was to determine the risk for falls after major orthopaedic surgery with peripheral nerve blockade. Electronic databases from inception through January 2012 were searched. Eligible studies evaluated falls after peripheral nerve blockade in adult patients undergoing major lower extremity orthopaedic surgery. Independent reviewers working in duplicate extracted study characteristics, validity, and outcomes data. The Peto odds ratio (OR) with 95% confidence intervals (CIs) were estimated from each study that compared continuous lumbar plexus blockade with non-continuous blockade or no blockade using a fixed effects model. Ten studies (4014 patients) evaluated the number of falls as an outcome. Five studies did not contain comparison groups. The meta-analysis of five studies [four randomized controlled trials (RCTs) and one cohort] compared continuous lumbar plexus blockade (631 patients) with non-continuous blockade or no blockade (964 patients). Fourteen falls occurred in the continuous lumbar plexus block group when compared with five falls within the non-continuous block or no block group (attributable risk 1.7%; number needed to harm 59). Continuous lumbar plexus blockade was associated with a statistically significant increase in the risk for falls [Peto OR 3.85; 95% CI (1.52, 9.72); P=0.005; I2=0%]. Evidence was low (cohort) to high (RCTs) quality. Continuous lumbar plexus blockade in adult patients undergoing major lower extremity orthopaedic surgery increases the risk for postoperative falls compared with non-continuous blockade or no blockade. However, attributable risk was not outside the expected probability of postoperative falls after orthopaedic surgery.
PMCID: PMC3600943  PMID: 23440367
accidental falls; anaesthesia, conduction; arthroplasty, replacement, hip; arthroplasty, replacement, knee; muscle weakness; nerve block
3.  Impact of perioperative dexamethasone on postoperative analgesia and side-effects: systematic review and meta-analysis 
BJA: British Journal of Anaesthesia  2012;110(2):191-200.
The analgesic efficacy and adverse effects of a single perioperative dose of dexamethasone are unclear. We performed a systematic review to evaluate the impact of a single i.v. dose of dexamethasone on postoperative pain and explore adverse events associated with this treatment.
MEDLINE, EMBASE, CINAHL, and the Cochrane Register were searched for randomized, controlled studies that compared dexamethasone vs placebo or an antiemetic in adult patients undergoing general anaesthesia and reported pain outcomes.
Forty-five studies involving 5796 patients receiving dexamethasone 1.25–20 mg were included. Patients receiving dexamethasone had lower pain scores at 2 h {mean difference (MD) −0.49 [95% confidence interval (CI): −0.83, −0.15]} and 24 h [MD −0.48 (95% CI: −0.62, −0.35)] after surgery. Dexamethasone-treated patients used less opioids at 2 h [MD −0.87 mg morphine equivalents (95% CI: −1.40 to −0.33)] and 24 h [MD −2.33 mg morphine equivalents (95% CI: −4.39, −0.26)], required less rescue analgesia for intolerable pain [relative risk 0.80 (95% CI: 0.69, 0.93)], had longer time to first dose of analgesic [MD 12.06 min (95% CI: 0.80, 23.32)], and shorter stays in the post-anaesthesia care unit [MD −5.32 min (95% CI: −10.49 to −0.15)]. There was no dose–response with regard to the opioid-sparing effect. There was no increase in infection or delayed wound healing with dexamethasone, but blood glucose levels were higher at 24 h [MD 0.39 mmol litre−1 (95% CI: 0.04, 0.74)].
A single i.v. perioperative dose of dexamethasone had small but statistically significant analgesic benefits.
PMCID: PMC3544008  PMID: 23220857
analgesics, opioid; dexamethasone; glucocorticoids; hyperglycaemia; pain, postoperative; surgical wound infection
4.  Perioperative central nervous system injury in neonates 
BJA: British Journal of Anaesthesia  2012;109(Suppl 1):i60-i67.
Anaesthetic-induced developmental neurotoxicity (AIDN) has been clearly established in laboratory animal models. The possibility of neurotoxicity during uneventful anaesthetic procedures in human neonates or infants has led to serious questions about the safety of paediatric anaesthesia. However, the applicability of animal data to clinical anaesthesia practice remains uncertain. The spectre of cerebral injury due to cerebral hypoperfusion, metabolic derangements, coexisting disease, and surgery itself further muddles the picture. Given the potential magnitude of the public health importance of this issue, the clinician should be cognisant of the literature and ongoing investigations on AIDN, and raise awareness of the risks of both surgery and anaesthesia.
PMCID: PMC3521998  PMID: 23242752
anaesthesia, paediatric; brain injury; paediatric; surgery
5.  Predictive performance of the Domino, Hijazi, and Clements models during low-dose target-controlled ketamine infusions in healthy volunteers 
British journal of anaesthesia  2007;98(5):10.1093/bja/aem063.
Healthy volunteers received low-dose target-controlled infusions (TCI) of ketamine controlled by the Domino model while cognitive function tests and functional neuroimaging were performed. The aim of the current study was to assess the predictive performance of the Domino model during these studies, and compare it with that of three other ketamine models.
Fifty-eight volunteers received ketamine administered by a TCI device on one or more occasions at target concentrations of either 50, 100, or 200 ng ml−1. At each target concentration, two or three venous blood samples were withdrawn during infusion, with a further sample after the infusion ended. Ketamine assays were performed by gas chromatography. The plasma concentration time courses predicted by the Hijazi, Clements 125, and Clements 250 models were calculated retrospectively, and the predictive performance of each of the models was assessed using Varvel methodology.
For the Domino model, bias, inaccuracy, wobble, and divergence were −2.7%, 33.9%, 24.2%, and 0.1463 % h−1, respectively. There was a systematic increase in performance error over time. The Clements 250 model performed best by all criteria, whereas the Hijazi model performed least well by all criteria except for bias.
Performance of the Domino model during control of low-dose ketamine infusions was sub-optimal. The Clements 250 model may be a better model for controlling low-dose TCI ketamine administration
PMCID: PMC3838936  PMID: 17389691
anaesthetics; i.v.; ketamine; pharmacokinetics
6.  Increased electroencephalographic gamma activity reveals awakening from isoflurane anaesthesia in rats 
BJA: British Journal of Anaesthesia  2012;109(5):782-789.
Animal studies often require reliable measures for anaesthetic drug effects. Lately, EEG-based depth of anaesthesia estimation has been widely applied to rat models. This study investigated the reliability of different EEG spectral properties in revealing awakening from isoflurane anaesthesia in rats.
Adult Wistar rats with previously implanted frontal epidural electrodes were anaesthetized using isoflurane. The anaesthesia was slowly lightened until awakening, as observed by the first spontaneous movement, after which anaesthesia was induced again by increasing the isoflurane concentration. EEG was recorded during the recovery and induction periods, and the spectrograms and 23 quantitative spectral parameters used in the depth of anaesthesia estimation were calculated from the signals.
The awakening was accompanied by a decrease in EEG activity at frequencies below 25 Hz, while the activity at higher frequencies (25–150 Hz) was increased. Whereas the behaviour of parameters used to measure activity in the lower frequencies was subject to variability between animals, the increase in higher frequency activity was more consistent, resulting in a statistically significant change in the relative gamma power parameters at the moment of awakening.
The increase in frontal relative gamma activity, especially in the 50–150 Hz frequency band, seems to be the most reliable EEG indicator for the awakening of a rat from isoflurane anaesthesia. A number of other spectral measures can also be used to detect this event. However, the role of gamma frequencies in the performance of these parameters is crucial.
PMCID: PMC3470445  PMID: 22907339
anaesthesia, depth; anaesthetics volatile, isoflurane; monitoring, depth of anaesthesia; monitoring, electroencephalography; rat
7.  Caveolae and propofol effects on airway smooth muscle 
BJA: British Journal of Anaesthesia  2012;109(3):444-453.
The i.v. anaesthetic propofol produces bronchodilatation. Airway relaxation involves reduced intracellular Ca2+ ([Ca2+]i) in airway smooth muscle (ASM) and lipid rafts (caveolae), and constitutional caveolin proteins regulate [Ca2+]i. We postulated that propofol-induced bronchodilatation involves caveolar disruption.
Caveolar fractions of human ASM cells were tested for propofol content. [Ca2+]i responses of ASM cells loaded with fura-2 were performed in the presence of 10 µM histamine with and without clinically relevant concentrations of propofol (10 and 30 μM and intralipid control). Effects on sarcoplasmic reticulum (SR) Ca2+ release were evaluated in zero extracellular Ca2+ using the blockers Xestospongin C and ryanodine. Store-operated Ca2+ entry (SOCE) after SR depletion was evaluated using established techniques. The role of caveolin-1 in the effect of propofol was tested using small interference RNA (siRNA) suppression. Changes in intracellular signalling cascades relevant to [Ca2+]i and force regulation were also evaluated.
Propofol was present in ASM caveolar fractions in substantial concentrations. Exposure to 10 or 30 µM propofol form decreased [Ca2+]i peak (but not plateau) responses to histamine by ∼40%, an effect persistent in zero extracellular Ca2+. Propofol effects were absent in caveolin-1 siRNA-transfected cells. Inhibition of ryanodine receptors prevented propofol effects on [Ca2+]i, while propofol blunted [Ca2+]i responses to caffeine. Propofol reduced SOCE, an effect also prevented by caveolin-1 siRNA. Propofol effects were associated with decreased caveolin-1 expression and extracellular signal-regulated kinase phosphorylation.
These novel data suggest a role for caveolae (specifically caveolin-1) in propofol-induced bronchodilatation. Due to its lipid nature, propofol may transiently disrupt caveolar regulation, thus altering ASM [Ca2+]i.
PMCID: PMC3415286  PMID: 22542538
bronchial smooth muscle; bronchodilatation; calcium regulation; caveolin; intravenous anaesthetic; signalling
8.  Risks for impaired cerebral autoregulation during cardiopulmonary bypass and postoperative stroke 
BJA: British Journal of Anaesthesia  2012;109(3):391-398.
Impaired cerebral autoregulation may predispose patients to cerebral hypoperfusion during cardiopulmonary bypass (CPB). The purpose of this study was to identify risk factors for impaired autoregulation during coronary artery bypass graft, valve surgery with CPB, or both and to evaluate whether near-infrared spectroscopy (NIRS) autoregulation monitoring could be used to identify this condition.
Two hundred and thirty-four patients were monitored with transcranial Doppler and NIRS. A continuous, moving Pearson's correlation coefficient was calculated between mean arterial pressure (MAP) and cerebral blood flow (CBF) velocity, and between MAP and NIRS data, to generate the mean velocity index (Mx) and cerebral oximetry index (COx), respectively. Functional autoregulation is indicated by an Mx and COx that approach zero (no correlation between CBF and MAP); impaired autoregulation is indicated by an Mx and COx approaching 1. Impaired autoregulation was defined as an Mx ≥0.40 at all MAPs during CPB.
Twenty per cent of patients demonstrated impaired autoregulation during CPB. Based on multivariate logistic regression analysis, time-averaged COx during CPB, male gender, , CBF velocity, and preoperative aspirin use were independently associated with impaired CBF autoregulation. Perioperative stroke occurred in six of 47 (12.8%) patients with impaired autoregulation compared with five of 187 (2.7%) patients with preserved autoregulation (P=0.011).
Impaired CBF autoregulation occurs in 20% of patients during CPB. Patients with impaired autoregulation are more likely than those with functional autoregulation to have perioperative stroke. Non-invasive monitoring autoregulation may provide an accurate means to predict impaired autoregulation.
Clinical trials registration. (NCT00769691).
PMCID: PMC3415287  PMID: 22661748
cardiac surgery; cardiopulmonary bypass; cerebral autoregulation; stroke
9.  Single sevoflurane exposure decreases neuronal nitric oxide synthase levels in the hippocampus of developing rats 
BJA: British Journal of Anaesthesia  2012;109(2):225-233.
The use of general anaesthetics in young children and infants has raised concerns regarding the adverse effects of these drugs on brain development. Sevoflurane might have harmful effects on the developing brain; however, these effects have not been well investigated.
Postnatal day 7 (P7) Sprague–Dawley rats were continuously exposed to 2.3% sevoflurane for 6 h. We used the Fox battery test and Morris water maze (MWM) to examine subsequent neurobehavioural performance. Cleaved caspase-3 and neuronal nitric oxide synthase (nNOS) were quantified by immunoblotting, and the Nissl staining was used to observe the histopathological changes in the hippocampus.
A single 6 h sevoflurane exposure at P7 rats resulted in increased cleaved caspase-3 expression and decreased nNOS levels in the hippocampus, and induced the loss of pyramidal neurones in the CA1 and CA3 subfields of the hippocampus at P7–8. These changes were accompanied by temporal retardation of sensorimotor reflexes. However, neither the Fox battery test at P1–21 nor the MWM test at P28–32 showed differences between the air- and sevoflurane-treated groups.
Although early exposure to sevoflurane increases activated caspase-3 expression and neuronal loss and decreases nNOS in the neonatal hippocampus, it does not affect subsequent neurobehavioural performances in juvenile rats.
PMCID: PMC3393078  PMID: 22535834
anaesthetic, sevoflurane; caspase 3; hippocampus; memory; neuronal nitric oxide synthase; sevoflurane
10.  Electroacupuncture inhibition of hyperalgesia in an inflammatory pain rat model: involvement of distinct spinal serotonin and norepinephrine receptor subtypes 
BJA: British Journal of Anaesthesia  2012;109(2):245-252.
Although acupuncture analgesia is well documented, its mechanisms have not been thoroughly clarified. We previously showed that electroacupuncture (EA) activates supraspinal serotonin- and norepinephrine-containing neurones that project to the spinal cord. This study investigates the involvement of spinal alpha(2)-adrenoceptors (α2-ARs) and 5-hydroxytryptamine (serotonin) receptors (5-HTRs) in EA effects on an inflammatory pain rat model.
Inflammatory hyperalgesia was induced by injecting complete Freund's adjuvant (CFA, 0.08 ml) into the plantar surface of one hind paw and assessed by paw withdrawal latency (PWL) to a noxious thermal stimulus. The selective α2a-AR antagonist BRL-44408, α2b-AR antagonist imiloxan hydrochloride, 5-HT2B receptor (5-HT2BR) antagonist SB204741, 5-HT3R antagonist LY278584, or 5-HT1AR antagonists NAN-190 hydrobromide, or WAY-100635 were intrathecally administered 20 min before EA or sham EA, which was given 2 h post-CFA at acupoint GB30.
EA significantly increased PWL compared with sham [7.20 (0.46) vs 5.20 (0.43) s]. Pretreatment with α2a-AR [5.35 (0.45) s] or 5-HT1AR [5.22 (0.38) s] antagonists blocked EA-produced anti-hyperalgesia; α2b-AR, 5-HT2BR, and 5-HT3R antagonist pretreatment did not. Sham plus these antagonists did not significantly change PWL compared with sham plus vehicle, indicating that the antagonists had little effect on PWL. Immunohistochemical staining demonstrated that α2a-ARs are on primary afferents and 5-HT1ARs are localized in N-methyl-d-aspartic acid (NMDA) subunit NR1-containing neurones in the spinal dorsal horn.
The data show that α2a-ARs and 5-HT1ARs are involved in the EA inhibition of inflammatory pain and that the NMDA receptors are involved in EA action.
PMCID: PMC3393079  PMID: 22628394
acupuncture; norepinephrine; pain; serotonin; spinal cord
12.  Imaging pain: a potent means for investigating pain mechanisms in patients 
Chronic pain is a state of physical suffering strongly associated with feelings of anxiety, depression and despair. Disease pathophysiology, psychological state, and social milieu can influence chronic pain, but can be difficult to diagnose based solely on clinical presentation. Here, we review brain neuroimaging research that is shaping our understanding of pain mechanisms, and consider how such knowledge might lead to useful diagnostic tools for the management of persistent pain in individual patients.
PMCID: PMC3690317  PMID: 23794647
chronic pain; neuroimaging, magnetic resonance imaging, functional
13.  Ventilatory responses after major surgery and high dependency care 
BJA: British Journal of Anaesthesia  2012;108(5):864-871.
Disturbed breathing during sleep, with episodic upper airway obstruction, is frequent after major surgery. Ventilatory responses to hypercapnia and hypoxia during episodes of airway obstruction are difficult to investigate because the usual measure, that of ventilation, has been attenuated by the obstruction. We simulated the blood gas stimulus associated with obstruction to allow investigation of the responses.
To assess ventilatory responses, we studied 19 patients, mean age 59 (19–79), first at discharge from high dependency care after major abdominal surgery and then at surgical review, ∼6 weeks later. Exhaled gas was analysed and inspired gas adjusted to simulate changes that would occur during airway obstruction. Changes in ventilation were measured over the following 45–70 s. Studies were done from air breathing if possible, and also from an increased inspired oxygen concentration.
During simulated obstruction, hypercapnia developed similarly in all the test conditions. Arterial oxygen saturation decreased significantly more rapidly when the test was started from air breathing. The mean ventilatory response was 5.8 litre min−2 starting from air breathing and 4.5 litre min−2 with oxygen breathing. The values 6 weeks later were 5.9 and 4.3 litre min−2, respectively (P=0.05, analysis of variance). There was no statistical difference between the responses starting from air and those on oxygen.
After major surgery, ventilatory responses to hypercapnia and hypoxaemia associated with airway obstruction are small and do not improve after 6 weeks. With air breathing, arterial oxygen desaturation during simulated rebreathing is substantial.
PMCID: PMC3325049  PMID: 22369766
general surgery; pulmonary ventilation; respiratory insufficiency
14.  Impact of phenylephrine administration on cerebral tissue oxygen saturation and blood volume is modulated by carbon dioxide in anaesthetized patients† 
BJA: British Journal of Anaesthesia  2012;108(5):815-822.
Multiple studies have shown that cerebral tissue oxygen saturation () is decreased after phenylephrine treatment. We hypothesized that the negative impact of phenylephrine administration on is affected by arterial blood carbon dioxide partial pressure () because CO2 is a powerful modulator of cerebrovascular tone.
In 14 anaesthetized healthy patients, i.v. phenylephrine bolus was administered to increase the mean arterial pressure ∼20–30% during hypocapnia, normocapnia, and hypercapnia. and cerebral blood volume (CBV) were measured using frequency domain near-infrared spectroscopy, a quantitative technology. Data collection occurred before and after each treatment.
Phenylephrine caused a significant decrease in during hypocapnia [=−3.4 (1.5)%, P<0.001], normocapnia [=−2.4 (1.5)%, P<0.001], and hypercapnia [=−1.4 (1.5)%, P<0.01]. Decreases in were significantly different between hypocapnia, normocapnia, and hypercapnia (P<0.001). Phenylephrine also caused a significant decrease in CBV during hypocapnia (P<0.01), but not during normocapnia or hypercapnia.
The negative impact of phenylephrine treatment on and CBV is intensified during hypocapnia while blunted during hypercapnia.
PMCID: PMC3325051  PMID: 22391890
carbon dioxide; cerebral blood volume; cerebral tissue oxygen saturation; modulation; phenylephrine
15.  Impact of the World Health Organization's Surgical Safety Checklist on safety culture in the operating theatre: a controlled intervention study 
BJA: British Journal of Anaesthesia  2013;110(5):807-815.
Positive changes in safety culture have been hypothesized to be one of the mechanisms behind the reduction in mortality and morbidity after the introduction of the World Health Organization's Surgical Safety Checklist (SSC). We aimed to study the checklist effects on safety culture perceptions in operating theatre personnel using a prospective controlled intervention design at a single Norwegian university hospital.
We conducted a study with pre- and post-intervention surveys using the intervention and control groups. The primary outcome was the effects of the Norwegian version of the SSC on safety culture perceptions. Safety culture was measured using the validated Norwegian version of the Hospital Survey on Patient Safety Culture. Descriptive characteristics of operating theatre personnel and checklist compliance data were also recorded. A mixed linear regression model was used to assess changes in safety culture.
The response rate was 61% (349/575) at baseline and 51% (292/569) post-intervention. Checklist compliance ranged from 77% to 85%. We found significant positive changes in the checklist intervention group for the culture factors ‘frequency of events reported’ and ‘adequate staffing’ with regression coefficients at −0.25 [95% confidence interval (CI), −0.47 to −0.07] and 0.21 (95% CI, 0.07–0.35), respectively. Overall, the intervention group reported significantly more positive culture scores—including at baseline.
Implementation of the SSC had rather limited impact on the safety culture within this hospital.
PMCID: PMC3630285  PMID: 23404986
checklist; safety; safety climate; safety culture; surgery
16.  Time course of haemostatic effects of fibrinogen concentrate administration in aortic surgery 
BJA: British Journal of Anaesthesia  2013;110(6):947-956.
There is currently a contrast between the demonstrated benefits of fibrinogen concentrate in correcting bleeding and reducing transfusion, and its perceived thrombogenic potential. This analysis evaluates the effects of fibrinogen concentrate on coagulation up to 12 days after administration during aortic surgery.
We performed a post hoc analysis of a prospective, randomized, double-blind, controlled trial of fibrinogen concentrate as first-line haemostatic therapy in aortic surgery. After cardiopulmonary bypass (CPB) and protamine administration, subjects with coagulopathic bleeding received fibrinogen concentrate or placebo. The placebo group received allogeneic blood products, including fresh-frozen plasma (FFP; n=32); the fibrinogen concentrate group received fibrinogen concentrate alone (FC; n=14), or fibrinogen concentrate followed by allogeneic blood products (FC+FFP; n=15). Plasma fibrinogen, fibrin-based clotting (ROTEM®-based FIBTEM assay), and peri- and postoperative haematological and coagulation parameters were compared.
Plasma fibrinogen and FIBTEM maximum clot firmness (MCF) decreased ∼50% during CPB but were corrected by FC or FC+FFP. At last suture, the highest values for plasma fibrinogen (360 mg dl−1) and FIBTEM MCF (22 mm) were within normal ranges—below the acute phase increases observed after surgery. In patients receiving only FFP as a source of fibrinogen, these parameters recovered marginally by last suture (P<0.001 vs FC and FC+FFP). All groups displayed comparable haemostasis at 24 h post-surgery. Fibrinogen concentrate did not cause alterations of other haemostasis parameters.
Fibrinogen concentrate provided specific, significant, short-lived increases in plasma fibrinogen and fibrin-based clot firmness after aortic surgery.
PMCID: PMC3657602  PMID: 23388508
blood coagulation tests; cardiopulmonary bypass; fibrin; fibrinogen; plasma
17.  Antioxidants that protect mitochondria reduce interleukin-6 and oxidative stress, improve mitochondrial function, and reduce biochemical markers of organ dysfunction in a rat model of acute sepsis 
BJA: British Journal of Anaesthesia  2013;110(3):472-480.
Sepsis-induced organ failure is the major cause of death in critical care units, and is characterized by a massive dysregulated inflammatory response and oxidative stress. We investigated the effects of treatment with antioxidants that protect mitochondria (MitoQ, MitoE, or melatonin) in a rat model of lipopolysaccharide (LPS) plus peptidoglycan (PepG)-induced acute sepsis, characterized by inflammation, mitochondrial dysfunction and early organ damage.
Anaesthetized and ventilated rats received an i.v. bolus of LPS and PepG followed by an i.v. infusion of MitoQ, MitoE, melatonin, or saline for 5 h. Organs and blood were then removed for determination of mitochondrial and organ function, oxidative stress, and key cytokines.
MitoQ, MitoE, or melatonin had broadly similar protective effects with improved mitochondrial respiration (P<0.002), reduced oxidative stress (P<0.02), and decreased interleukin-6 levels (P=0.0001). Compared with control rats, antioxidant-treated rats had lower levels of biochemical markers of organ dysfunction, including plasma alanine amino-transferase activity (P=0.02) and creatinine concentrations (P<0.0001).
Antioxidants that act preferentially in mitochondria reduce mitochondrial damage and organ dysfunction and decrease inflammatory responses in a rat model of acute sepsis.
PMCID: PMC3570068  PMID: 23381720
co-enzyme Q10; interleukin-6; interleukin-10; melatonin; sepsis; tocopherol
19.  Haemostatic monitoring during postpartum haemorrhage and implications for management 
BJA: British Journal of Anaesthesia  2012;109(6):851-863.
Postpartum haemorrhage (PPH) is a major risk factor for maternal morbidity and mortality. PPH has numerous causative factors, which makes its occurrence and severity difficult to predict. Underlying haemostatic imbalances such as consumptive and dilutional coagulopathies may develop during PPH, and can exacerbate bleeding and lead to progression to severe PPH. Monitoring coagulation status in patients with PPH may be crucial for effective haemostatic management, goal-directed therapy, and improved outcomes. However, current PPH management guidelines do not account for the altered baseline coagulation status observed in pregnant patients, and the appropriate transfusion triggers to use in PPH are unknown, due to a lack of high-quality studies specific to this area. In this review, we consider the evidence for the use of standard laboratory-based coagulation tests and point-of-care viscoelastic coagulation monitoring in PPH. Many laboratory-based tests are unsuitable for emergency use due to their long turnaround times, so have limited value for the management of PPH. Emerging evidence suggests that viscoelastic monitoring, using thrombelastography- or thromboelastometry-based tests, may be useful for rapid assessment and for guiding haemostatic therapy during PPH. However, further studies are needed to define the ranges of reference values that should be considered ‘normal’ in this setting. Improving awareness of the correct application and interpretation of viscoelastic coagulation monitoring techniques may be critical in realizing their emergency diagnostic potential.
PMCID: PMC3498756  PMID: 23075633
blood coagulation tests; point-of-care systems; postpartum haemorrhage; thrombelastography
20.  Implementation of the quality management system improves postoperative pain treatment: a prospective pre-/post-interventional questionnaire study 
An organizational approach is proposed as an immediate solution for improving postoperative pain (POP) management. The aim was to evaluate the clinical effectiveness of a quality management system (QMS), based on procedure-specific, multimodal analgesic protocols, modified to meet the individual patients’ requirements.
Patients from the orthopaedic, gynaecological, visceral, and trauma surgery departments of the university hospital were involved in two prospective surveys. Survey 1 was performed at baseline and survey 2 was performed after the implementation of QMS within an interval of 1 year. The patients were asked to report pain intensity on the visual rating scale, incidence of analgesia-related side-effects, and incidence of pain interference with the items of life quality and their satisfaction with the treatment of POP.
Patients from Survey 2 (n=251) reported 25–30% less pain than those from Survey 1 (n=269) (P<0.0001). Nausea was reported by 40% of the patients from Survey 1 vs 17% from Survey 2, vomiting by 25 vs 11% and fatigue by 76% in Survey 1 vs 30% in Survey 2 (P<0.0001). Life quality and patients’ satisfaction improved in Survey 2 vs Survey 1 (P<0.001).
The implementation of QMS allowed the reduction in POP intensity with a simultaneous decrease in analgesia-related side-effects. This has led to an increased quality of life and patient satisfaction.
PMCID: PMC3520148  PMID: 23048069
adverse effects; analgesia; pain, postoperative; quality management
21.  Do technical skills correlate with non-technical skills in crisis resource management: a simulation study 
BJA: British Journal of Anaesthesia  2012;109(5):723-728.
Both technical skills (TS) and non-technical skills (NTS) are key to ensuring patient safety in acute care practice and effective crisis management. These skills are often taught and assessed separately. We hypothesized that TS and NTS are not independent of each other, and we aimed to evaluate the relationship between TS and NTS during a simulated intraoperative crisis scenario.
This study was a retrospective analysis of performances from a previously published work. After institutional ethics approval, 50 anaesthesiology residents managed a simulated crisis scenario of an intraoperative cardiac arrest secondary to a malignant arrhythmia. We used a modified Delphi approach to design a TS checklist, specific for the management of a malignant arrhythmia requiring defibrillation. All scenarios were recorded. Each performance was analysed by four independent experts. For each performance, two experts independently rated the technical performance using the TS checklist, and two other experts independently rated NTS using the Anaesthetists' Non-Technical Skills score.
TS and NTS were significantly correlated to each other (r=0.45, P<0.05).
During a simulated 5 min resuscitation requiring crisis resource management, our results indicate that TS and NTS are related to one another. This research provides the basis for future studies evaluating the nature of this relationship, the influence of NTS training on the performance of TS, and to determine whether NTS are generic and transferrable between crises that require different TS.
PMCID: PMC3470444  PMID: 22850221
cardiopulmonary resuscitation; clinical competence; medical education; patient simulation
22.  Patient blood management in Europe 
Preoperative anaemia is common in patients undergoing orthopaedic and other major surgery. Anaemia is associated with increased risks of postoperative mortality and morbidity, infectious complications, prolonged hospitalization, and a greater likelihood of allogeneic red blood cell (RBC) transfusion. Evidence of the clinical and economic disadvantages of RBC transfusion in treating perioperative anaemia has prompted recommendations for its restriction and a growing interest in approaches that rely on patients' own (rather than donor) blood. These approaches are collectively termed ‘patient blood management’ (PBM). PBM involves the use of multidisciplinary, multimodal, individualized strategies to minimize RBC transfusion with the ultimate goal of improving patient outcomes. PBM relies on approaches (pillars) that detect and treat perioperative anaemia and reduce surgical blood loss and perioperative coagulopathy to harness and optimize physiological tolerance of anaemia. After the recent resolution 63.12 of the World Health Assembly, the implementation of PBM is encouraged in all WHO member states. This new standard of care is now established in some centres in the USA and Austria, in Western Australia, and nationally in the Netherlands. However, there is a pressing need for European healthcare providers to integrate PBM strategies into routine care for patients undergoing orthopaedic and other types of surgery in order to reduce the use of unnecessary transfusions and improve the quality of care. After reviewing current PBM practices in Europe, this article offers recommendations supporting its wider implementation, focusing on anaemia management, the first of the three pillars of PBM.
PMCID: PMC3374574  PMID: 22628393
anaemia; outcome; patient blood management; transfusion
23.  High STOP-Bang score indicates a high probability of obstructive sleep apnoea 
BJA: British Journal of Anaesthesia  2012;108(5):768-775.
The STOP-Bang questionnaire is used to screen patients for obstructive sleep apnoea (OSA). We evaluated the association between STOP-Bang scores and the probability of OSA.
After Institutional Review Board approval, patients who visited the preoperative clinics for a scheduled inpatient surgery were approached for informed consent. Patients answered STOP questionnaire and underwent either laboratory or portable polysomnography (PSG). PSG recordings were scored manually. The BMI, age, neck circumference, and gender (Bang) were documented. Over 4 yr, 6369 patients were approached and 1312 (20.6%) consented. Of them, 930 completed PSG, and 746 patients with complete data on PSG and STOP-Bang questionnaire were included for data analysis.
The median age of 746 patients was 60 yr, 49% males, BMI 30 kg m−2, and neck circumference 39 cm. OSA was present in 68.4% with 29.9% mild, 20.5% moderate, and 18.0% severe OSA. For a STOP-Bang score of 5, the odds ratio (OR) for moderate/severe and severe OSA was 4.8 and 10.4, respectively. For STOP-Bang 6, the OR for moderate/severe and severe OSA was 6.3 and 11.6, respectively. For STOP-Bang 7 and 8, the OR for moderate/severe and severe OSA was 6.9 and 14.9, respectively. The predicted probabilities for moderate/severe OSA increased from 0.36 to 0.60 as the STOP-Bang score increased from 3 to 7 and 8.
In the surgical population, a STOP-Bang score of 5–8 identified patients with high probability of moderate/severe OSA. The STOP-Bang score can help the healthcare team to stratify patients for unrecognized OSA, practice perioperative precautions, or triage patients for diagnosis and treatment.
PMCID: PMC3325050  PMID: 22401881
mass screening; obstructive/ep (epidemiology); polysomnography; prospective studies; questionnaires; sleep apnoea; snoring/di (diagnosis); snoring/ep (epidemiology)
24.  Early childhood general anaesthesia exposure and neurocognitive development 
BJA: British Journal of Anaesthesia  2010;105(Suppl 1):i61-i68.
A great deal of concern has recently arisen regarding the safety of anaesthesia in infants and children. There is mounting and convincing preclinical evidence in rodents and non-human primates that anaesthetics in common clinical use are neurotoxic to the developing brain in vitro and cause long-term neurobehavioural abnormalities in vivo. An estimated 6 million children (including 1.5 million infants) undergo surgery and anaesthesia each year in the USA alone, so the clinical relevance of anaesthetic neurotoxicity is an urgent matter of public health. Clinical studies that have been conducted on the long-term neurodevelopmental effects of anaesthetic agents in infants and children are retrospective analyses of existing data. Two large-scale clinical studies are currently underway to further address this issue. The PANDA study is a large-scale, multisite, ambi-directional sibling-matched cohort study in the USA. The aim of this study is to examine the neurodevelopmental effects of exposure to general anaesthesia during inguinal hernia surgery before 36 months of age. Another large-scale study is the GAS study, which will compare the neurodevelopmental outcome between two anaesthetic techniques, general sevoflurane anaesthesia and regional anaesthesia, in infants undergoing inguinal hernia repair. These study results should contribute significant information related to anaesthetic neurotoxicity in children.
PMCID: PMC3000523  PMID: 21148656
anaesthesia, paediatric; children; neurocognitive outcome; neurotoxicity; risk
25.  Postoperative delirium and cognitive dysfunction 
BJA: British Journal of Anaesthesia  2009;103(Suppl 1):i41-i46.
Postoperative delirium and cognitive dysfunction (POCD) are topics of special importance in the geriatric surgical population. They are separate entities, whose relationship has yet to be fully elucidated. Although not limited to geriatric patients, the incidence and impact of both are more profound in geriatric patients. Delirium has been shown to be associated with longer and more costly hospital course and higher likelihood of death within 6 months or postoperative institutionalization. POCD has been associated with increased mortality, risk of leaving the labour market prematurely, and dependency on social transfer payments. Here, we review their definitions and aetiology, and discuss treatment and prevention in elderly patients undergoing major non-cardiac surgery. Good basic care demands identification of at-risk patients, awareness of common perioperative aggravating factors, simple prevention interventions, recognition of the disease states, and basic treatments for patients with severe hyperactive manifestations.
PMCID: PMC2791855  PMID: 20007989
age factors; anaesthesia, geriatric; brain; complications

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