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2.  Anticipation of the difficult airway: preoperative airway assessment, an educational and quality improvement tool 
BJA: British Journal of Anaesthesia  2013;111(2):276-285.
Assessment of the potentially difficult airway (DA) is a critical aspect of resident education. We investigated the impact of a new assessment form on airway prediction and management by anaesthesia residents. We hypothesized that residents would demonstrate improvement in evaluation of DAs over the study duration.
After IRB approval, anaesthesia residents were randomized into two groups: control (existing form) and experimental (new form). Data were collected prospectively from August 2008 to May 2010 on all non-obstetric adult patients undergoing non-emergent surgery.
Eight thousand three hundred and sixty-four independent preoperative assessments were collected and 8075 were analysed. The experimental group had the higher completion rate than the control group (94.3% vs 84.3%, P=0.001). DA prediction was higher for the control group (71.2%) compared with the experimental group (69.1%; P=0.032). A significant improvement in prediction rates was found over time for the experimental group (likelihood estimate=0.00068, P=0.031).
The use of a comprehensive airway assessment did not improve resident ability to predict a DA in an academic, tertiary-based hospital, anaesthesiology residency training programme.
PMCID: PMC3711391  PMID: 23471752
airway; education, medical students
3.  Variation of bispectral index under TIVA with propofol in a paediatric population 
In this prospective observational study, we aim to explore the relationship between age and BIS values at different plasma concentrations of propofol.
Fifty children aged from 3 to 15 years were included. Anaesthesia was induced using a target controlled infusion of propofol with the Kataria pharmacokinetic model together with a bolus of remifentanil followed by a continuous infusion rate at 0.2 mcg·kg−1·min−1. Target plasma propofol concentration was initially stabilized to 6 mcg·ml−1 and continued for 6 minutes. The target was then decreased and stabilized to 4 mcg·ml−1 and then to 2 mcg·ml−1. BIS values, plasma propofol concentration and EEG were continuously recorded. In order to explore the relationship between variations in propofol concentration and the EEG bispectrum, we used a Multiple Correspondence Analysis (MCA). Results are shown in median (range).
We found no statistical difference between BIS values with propofol 6 mcg·ml−1 23 (12–40) and propofol 4 mcg·ml−1 28 (9–67). At 2 mcg·ml−1, BIS was significantly different 52 (24–71) but a significant correlation between the age of children and BIS values was found (r2=0.66; p<0.01). There was little change in children’s position between 6 mcg·ml−1 and 4 mcg·ml−1 in the structure model of the MCA. From 4 mcg·ml−1 to 2 mcg·ml−1 the position of children moved only on axis 2.
These results showed the difficulty to interpret BIS values because of the absence of significant change for higher plasma propofol concentration variation or because of the link with age for the lower plasma concentration.
PMCID: PMC2657834  PMID: 18070785
Adolescent; Aging; physiology; Anesthetics, Intravenous; administration & dosage; blood; pharmacology; Blood Pressure; drug effects; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Administration Schedule; Electroencephalography; drug effects; Heart Rate; drug effects; Humans; Monitoring, Intraoperative; methods; Propofol; administration & dosage; blood; pharmacology; Prospective Studies; anaesthesia; depth; anaesthesia; paediatric; anaesthetics; i.v.; propofol; monitoring; bispectral index; bispectrum; plasma concentration; pharmacokinetic model; remifentanil
4.  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
5.  Block-Dependent Sedation during Epidural Anaesthesia is Associated with Delayed Brainstem Conduction 
British journal of anaesthesia  2004;93(2):228-234.
Neuraxial anaesthesia produces a sedative and anesthetic-sparing effect. Recent evidence suggests that spinal cord anaesthesia modifies reticulo-thalamo-cortical arousal by decreasing afferent sensory transmission. We hypothesized that epidural anaesthesia produces sensory deafferentation-dependent sedation that is associated with impairment of brainstem transmission. We used brainstem auditory evoked potentials (BAEP) to evaluate reticular function in 11 volunteers. Epidural anaesthesia was induced with 2% 2-chloroprocaine. Hemodynamic and respiratory responses, sensory block level, sedation depth and BAEP were assessed throughout induction and resolution of epidural anaesthesia. Sedation was evaluated using verbal rating score (VRS), observer's assessment alertness/sedation (OAA/S) score, and bispectral index (BIS). Prediction probability (PK) was used to associate sensory block with sedation, as well as BIS with other sedation measures. Spearman rank order correlation was used to associate block level and sedation with the absolute and interpeak BAEP latencies. Sensory block level significantly predicted VRS (PK = 0.747), OAA/S score (PK = 0.748) and BIS. Bispectral index predicted VRS and OAA/S score (PK = 0.728). The latency of wave III of BAEP significantly correlated with sedation level (rho = 0.335, P < 0.01) and sensory block (rho = 0.394, P < 0.01). The other BAEP parameters did not change during epidural anaesthesia. Hemodynamic and respiratory responses remained stable throughout the study. Sedation during epidural anaesthesia depends on sensory block level and is associated with detectable block-dependent alterations in the brainstem auditory evoked responses. Sensory deafferentation may reduce CNS alertness through mechanisms related to brainstem neural activity.
PMCID: PMC1361808  PMID: 15220178
Afferentation theory; Brainstem auditory evoked potentials; Chloroprocaine; Deafferentation; Epidural anaesthesia; Sedation; Sensory block
6.  Neuromuscular pharmacodynamics of mivacurium in adults with major burns 
BJA: British Journal of Anaesthesia  2011;106(5):675-679.
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.
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.
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.
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.
PMCID: PMC3077750  PMID: 21354998
neuromuscular relaxants, mivacurium; pharmacodynamics; trauma, burns
7.  The impact of age on bispectral index values and EEG bispectrum during anaesthesia with desflurane and halothane in children 
British Journal of Anaesthesia  2006;96(4):480-485.
The relationship between end-tidal sevoflurane concentration, BIS and the EEG bispectrum in children appears dependent on age. The aim of this study was to quantify the BIS values at 1 MAC for desflurane and halothane, and explore the relationship with age for these anaesthetic agents in children.
ECG, EEG and BIS were recorded continuously during the anaesthesia of ninety children aged 6–170 months requiring elective surgery. Fifty children were anaesthetised with desflurane, and forty children with halothane. Recordings were performed through to a steady state of 2 MAC, and thereafter at 1 MAC and 0.5 MAC respectively. The bispectrum of the EEG was estimated using MATLAB© software. For analysis, a multiple correspondence analysis (MCA) was used.
At the steady state of 1 MAC, BIS values were significantly higher with halothane 62 (43–80) compared to desflurane 34 (18–64). BIS values were significantly correlated to age in both groups: DES (r2=0.57; p<0.01) and HALO (r2=0.48; p<0.01). Changes in position in the structured model of the MCA (dependent on the pattern of the EEG bispectrum) were different for the two volatile anaesthetic agents.
BIS values are linked to age of children irrespective of the volatile anaesthetic agent used. In children, the difference in BIS values for different agents at the same MAC can be explained by the specific effect on the EEG bispectrum induced by each anaesthetic agent, bringing into question the ability of the EEG bispectrum to accurately determine depth of anaesthesia in children.
PMCID: PMC2034405  PMID: 16500950
Adolescent; Age Factors; Anesthetics, Inhalation; pharmacology; Body Weight; physiology; Child; Child, Preschool; Electrocardiography; drug effects; Electroencephalography; drug effects; Female; Halothane; pharmacology; Humans; Infant; Isoflurane; analogs & derivatives; pharmacology; Male; Monitoring, Intraoperative; methods; Depth of Anesthesia; EEG; Bispectrum; PCA; Factorial Analysis; Classification; Anesthesia; BIS; Monitoring
8.  Haemodynamic effects of remifentanil in children with and without intravenous atropine. An echocardiographic study 
Remifentanil is known to cause bradycardia and hypotension. We aimed to characterize the haemodynamic profile of remifentanil during sevoflurane anaesthesia in children with or without atropine.
Forty children who required elective surgery received inhalational induction of anaesthesia using 8% sevoflurane. They were allocated randomly to receive either atropine, 20 mg kg−1 (atropine group) or Ringer’s lactate (control group) after 10 min of steady-state 1 MAC sevoflurane anaesthesia (baseline). Three minutes later (T0), all children received remifentanil 1 mg kg−1 injected over a 60 s period, followed by an infusion of 0.25 mg kg−1 min−1 for 10 min then 0.5 mg kg−1 min−1 for 10 min. Haemodynamic variables and echocardiographic data were determined at baseline, T0, T5, T10, T15 and T20 min.
Remifentanil caused a significant decrease in heart rate compared with the T0 value, which was greater at T20 than T10 in the two groups: however, the values at T10 and T20 were not significantly different from baseline in the atropine group. In comparison with T0, there was a significant fall in blood pressure in the two groups. Remifentanil caused a significant decrease in the cardiac index with or without atropine. Remifentanil did not cause variation in stroke volume (SV). In both groups, a significant increase in systemic vascular resistance occurred after administration of remifentanil. Contractility decreased significantly in the two groups, but this decrease remained moderate (between −2 and +2 SD).
Remifentanil produced a fall in blood pressure and cardiac index, mainly as a result of a fall in heart rate. Although atropine was able to reduce the fall in heart rate, it did not completely prevent the reduction in cardiac index.
PMCID: PMC4767884  PMID: 15486003
Anaesthesia, paediatric; Anaesthetics i.v., remifentanil; Heart, myocardial contractility; Heart, myocardial function; Measurement techniques, echocardiography; Adjuvants, Anesthesia; Adolescent; Depression, Chemical; Echocardiography, Doppler; Female; Heart Rate; Hemodynami; Anesthetics, Combined; Anesthetics, Inhalation; Anesthetics, Intravenous; Atropine; Blood Pressure; Cardiac Output; Child; Child, Preschool
9.  Increased μ-opioid receptor expression in metastatic lung cancer 
BJA: British Journal of Anaesthesia  2014;113(Suppl 1):i103-i108.
We and others have previously demonstrated that the μ-opioid receptor (MOR) is overexpressed in several human malignancies. There is a seven-fold increase in MOR in cell lines of human lung cancer. In animal models, overexpression of MOR promotes tumour growth and metastasis. We, therefore, examined whether MOR expression is increased in metastatic lung cancer.
In this study, we examined the association between MOR expression and metastasis in archived biopsy samples from patients with lung cancer. Paraffin-embedded patient material was stained using MOR antibody and scored qualitatively by two independent pathologists using a four-point scale.
In human lung cancer and normal adjacent lung samples obtained from 34 lung cancer patients, MOR expression was increased significantly in cancer samples from patients with lung cancer compared with adjacent control tissue (P=0.0242). When the samples from patients with metastatic lung cancer were separated from the cohort of the total number of patients with lung cancer, we observed an approximately two-fold increase in MOR expression (P=0.0013).
The association between the expression of MOR and the progression of the tumour is consistent with the hypothesis of a direct effect of MOR on cancer progression.
PMCID: PMC4111280  PMID: 24920011
lung cancer; metastasis; methylnaltrexone; MOR; μ-opioid receptor
10.  Intrajugular balloon catheter reduces air embolism in vitro and in vivo 
BJA: British Journal of Anaesthesia  2015;114(6):973-978.
Neurosurgical procedures requiring a sitting position may put the patient at risk of a potentially life-threatening air embolism. Transient manual jugular venous compression limits further air entry in this situation. This study presents an alternative technique aimed at reducing the risk of air embolism.
In an in vitro model, an intrajugular balloon catheter was inserted to demonstrate that this device prevents air embolism. In an in vivo study, this device was bilaterally placed into jugular vessels in pigs. Using an ultrasound technique, blood flow was monitored and jugular venous pressure was recorded before and during cuff inflation. Air was applied proximally to the inflated cuffs to test the hypothesis that this novel device blocks air passage.
In vitro, the intrajugular balloon catheter reliably prevented further air entry (n=10). Additionally, accumulated air could be aspirated from an orifice of the catheter (n=10). In vivo, inflation of the catheter balloon completely obstructed venous blood flow (n=8). Bilateral inflation of the cuff significantly increased the proximal jugular venous pressure from 9.8 (2.4) mm Hg to 14.5 (2.5) mm Hg (n=8, P<0.05). Under conditions mimicking an air embolism, air passage across the inflated cuffs was prevented and 78 (20%) (n=6) of the air dose could be aspirated by the proximal orifice of the catheter.
These findings may serve as a starting point for the development of intrajugular balloon catheters designed to reduce the risk of air embolism in patients undergoing neurosurgery in a sitting position.
PMCID: PMC4436929  PMID: 25835025
anesthesia; catheterization; embolism, air; jugular veins; models, animal; neurosurgical procedures; patient positioning; posture
11.  Oral choline supplementation for postoperative pain 
BJA: British Journal of Anaesthesia  2013;111(2):249-255.
Activation of nicotinic receptors with nicotine has been shown to reduce post-surgical pain in clinical and preclinical studies. Choline is a selective agonist at α7-type nicotinic receptors that does not have addictive or sympathetic activating properties. It is anti-nociceptive in animal studies. We conducted a double-blind randomized trial of oral choline supplementation with lecithin to aid in the treatment of pain after gynaecological surgery.
Sixty women having open gynaecological surgery were randomly assigned to receive 20 g of lecithin before surgery or placebo. Plasma choline concentration and tumour necrosis factor (TNF) were measured. Pain report was the primary outcome measure.
We achieved a small but statistically significant increase in choline after surgery with oral supplementation. Plasma TNF was not decreased and pain report was not different between groups at rest or with movement. There were no adverse effects of treatment.
Oral supplementation with lecithin during the perioperative period resulted in very slow absorption and thus only a small increase in plasma choline was achieved. This concentration was inadequate to reduce TNF as has been shown in other studies. The absence of an anti-inflammatory effect was likely related to our failure to demonstrate efficacy in pain reduction.
PMCID: PMC3841409  PMID: 23568851
analgesia; anti-inflammatory agents; nutritional requirements; pain; pain measurement
14.  Supplemental Oxygen Does Not Reduce Postoperative Nausea and Vomiting after Thyroidectomy 
British journal of anaesthesia  2003;91(6):857-861.
Supplemental intra-operative oxygen (80%) halves the incidence of nausea and vomiting after open and laparoscopic abdominal surgery, perhaps by ameliorating the subtle intestinal ischemia associated with abdominal surgery. It is unlikely that thyroid surgery compromises intestinal perfusion. We therefore tested the hypothesis that supplemental perioperative oxygen does not reduce the risk of postoperative nausea and vomiting (PONV) after thyroidectomy. As a positive control, we simultaneously evaluated the anti-nausea efficacy of droperidol. One hundred and fifty patients undergoing thyroidectomy were given sevoflurane anaesthesia. After induction, patients were randomly assigned to the following treatments: 1) 30% oxygen, balance nitrogen; 2) 80% oxygen, balance nitrogen; or 3) 30% oxygen with droperidol 0.625 mg. The overall incidence of nausea during the first 24 postoperative hours was 48% in the patients given 30% oxygen, 46% in those given 80% oxygen, and 22% in those given droperidol (P = 0.004). There were no significant differences between the 30% and 80% oxygen groups in incidence or severity of PONV, the need for rescue anti-emetics, or patient satisfaction. Droperidol significantly shortened the time to first meal. Supplemental oxygen was ineffective in preventing nausea and vomiting after thyroidectomy, but droperidol halved the incidence.
PMCID: PMC1343506  PMID: 14633758
Anaesthesia; droperidol; oxygen; postoperative complications: nausea and vomiting; surgery: thyroidectomy
15.  Demystifying propensity scores 
PMCID: PMC3854550  PMID: 24318697
16.  Psychosocial interventions for managing pain in older adults: outcomes and clinical implications† 
Interest in the use of psychosocial interventions to help older adults manage pain is growing. In this article, we review this approach. The first section reviews the conceptual background for psychosocial interventions with a special emphasis on the biopsychosocial model of pain. The second section highlights three psychosocial interventions used with older adults: cognitive behavioural therapy, emotional disclosure, and mind–body interventions (specifically mindfulness-based stress reduction and yoga). The final section of the paper highlights important future directions for work in this area.
PMCID: PMC3690316  PMID: 23794650
age; chronic pain
17.  Impact of anaesthetics and surgery on neurodevelopment: an update 
BJA: British Journal of Anaesthesia  2013;110(Suppl 1):i53-i72.
Accumulating preclinical and clinical evidence suggests the possibility of neurotoxicity from neonatal exposure to general anaesthetics. Here, we review the weight of the evidence from both human and animal studies and discuss the putative mechanisms of injury and options for protective strategies. Our review identified 55 rodent studies, seven primate studies, and nine clinical studies of interest. While the preclinical data consistently demonstrate robust apoptosis in the nervous system after anaesthetic exposure, only a few studies have performed cognitive follow-up. Nonetheless, the emerging evidence that the primate brain is vulnerable to anaesthetic-induced apoptosis is of concern. The impact of surgery on anaesthetic-induced brain injury has not been adequately addressed yet. The clinical data, comprising largely retrospective cohort database analyses, are inconclusive, in part due to confounding variables inherent in these observational epidemiological approaches. This places even greater emphasis on prospective approaches to this problem, such as the ongoing GAS trial and PANDA study.
PMCID: PMC3667344  PMID: 23542078
brain, anaesthesia, molecular effects; nerve, damage (postoperative); nerve, neurotransmitters; nerve, regeneration
18.  Reply from the authors 
BJA: British Journal of Anaesthesia  2014;112(6):1121-1123.
PMCID: PMC4020385  PMID: 24829427
19.  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
20.  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
21.  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
22.  Clonidine Produces a Dose-dependent Impairment of Baroreflex-mediated Thermoregulatory Responses to Positive End-expiratory Pressure in Anaesthetised Humans 
British journal of anaesthesia  2005;94(4):536-541.
Background. Perioperative hypothermia is common and results from anaesthetic-induced inhibition of thermoregulatory control. Hypothermia is blunted by baroreceptor unloading caused by positive end-expiratory pressure (PEEP) and is mediated by an increase in the vasoconstriction threshold. Premedication with clonidine impairs normal thermoregulatory control. We therefore determined the effect of clonidine on PEEP-induced hypothermia protection.
Methods. Core temperature was evaluated in patients undergoing combined general and epidural anaesthesia for lower abdominal surgery. They were assigned to an end-expiratory pressure of zero (ZEEP) or 10 cmH2O PEEP. The PEEP group was divided into three blinded subgroups: placebo (Clonidine-0), clonidine 150 μg (Clonidine-150), and clonidine 300 μg (Clonidine-300). Placebo or clonidine was given orally 30 minutes before surgery. We evaluated core temperature and thermoregulatory vasoconstriction. We also determined epinephrine, norepinephrine, and angiotensin II concentrations and plasma renin activity.
Results. Core temperature after 180 minutes of anaesthesia was 35.1 ± 0.1°C in the ZEEP group. PEEP significantly increased final core temperature to 35.8 ± 0.2°C (Clonidine-0 group). Clonidine produced a linear, dose-dependent impairment of PEEP-induced hypothermia protection: final core temperatures of 35.4 ± 0.1°C in the clonidine-150 group and 35.1 ± 0.2°C in the Clonidine-300 group. Similarly, clonidine produced a linear and dose-dependent reduction in vasoconstriction threshold: Clonidine-0=36.4 ± 0.1°C, Clonidine-150=35.8 ± 0.1°C, and Clonidine-300=35.4 ± 0.2°C. Plasma norepinephrine and angiotensin II concentrations and renin activity were consistent with the thermoregulatory responses.
Conclusion. Baroreceptor unloading by PEEP normally moderates perioperative hypothermia. However, clonidine premedication produces a linear, dose-dependent impairment of this benefit.
PMCID: PMC1362957  PMID: 15708868
baroreceptor reflex; clonidine; hypothermia; positive end-expiratory pressure (PEEP); thermoregulation
23.  Impact of age on both BIS values and EEG bispectrum during anaesthesia with sevoflurane in children 
British Journal of Anaesthesia  2005;94(6):810-820.
The aim of this study was to evaluate the potential relationship between age, BIS (Aspect™) and the EEG bispectrum during anesthesia with sevoflurane. BIS and raw EEG sampled at 400 Hz were recorded at a steady state of 1 MAC sevoflurane in 100 children, and during a decrease from 2 MAC to 0.5 MAC in a sub-group of 29 children. The bispectrum of the EEG was estimated on successive epochs of 20 seconds using MATLAB© software, independently of the Aspect™ device. For analysis, the bispectrum was divided into 36 frequencies of coupling (Pi) - the MatBis. A multiple correspondence analysis (MCA) was used to establish an underlying structure of the pattern of each individual’s MatBis at the steady state of 1 MAC. Clustering of children into homogeneous groups was conducted by a hierarchical ascending classification (HAC). The level of statistical significance was set at 0.05. At the steady state of 1 MAC sevoflurane, the BIS values for all 100 children ranged from 20 to 74 (median 40). Projection of both age and BIS value recorded at 1 MAC (T10) onto the structured model of the MCA showed them to be distributed along axis F1 of this model. In contrast, projection of children’s position during the decrease in sevoflurane concentration was linked to axis F2. At 1 MAC sevoflurane, six homogeneous groups of children were obtained through the HAC. Groups 5 (30 months; range 23–49) and 6 (18 months; range 6–180) were the younger children and group 1 (97 months; range 46–162) the older. Groups 5 and 6 had the highest median values of BIS (54; range 50–59)(55; range 26–74) and the group 1 the lowest values (29; range 22–37). The EEG bispectrum, as well as the BIS (Aspect XP™) measured at 1 MAC sevoflurane appeared to be strongly related to the age of children.
PMCID: PMC2043092  PMID: 15833781
Adolescent; Aging; physiology; Anesthetics, Inhalation; pharmacology; Body Weight; physiology; Child; Child, Preschool; Dose-Response Relationship, Drug; Electroencephalography; drug effects; Humans; Infant; Methyl Ethers; pharmacology; Monitoring, Intraoperative; methods; Signal Processing, Computer-Assisted; Depth of Anesthesia; EEG; Bispectrum; PCA; Classification; Factorial Analysis; BIS; Monitoring
24.  Morphine stimulates cancer progression and mast cell activation and impairs survival in transgenic mice with breast cancer 
BJA: British Journal of Anaesthesia  2014;113(Suppl 1):i4-i13.
Morphine stimulates angiogenesis and cancer progression in mice. We investigated whether morphine influences tumour onset, development, and animal model survival, and whether µ-opioid receptor (MOR), lymphangiogenesis, mast cell activation, and substance P (SP) are associated with the tumour-promoting effects of morphine.
Transgenic mice with a rat C3(1) simian virus 40 large tumour antigen fusion gene which demonstrate the developmental spectrum of human infiltrating ductal breast carcinoma were used. Mice were treated at different ages with clinically relevant doses of morphine or phosphate-buffered saline to determine the effect on tumour development and progression, and on mouse survival. Tumours were analysed for MOR, angiogenesis, lymphangiogenesis, SP, and mast cell activation by immunofluorescent- or laser scanning confocal-microscopy. Cytokine and SP levels were determined by enzyme-linked immunosorbent assay.
Morphine did not influence tumour development when given before the onset of tumour appearance, but significantly promoted progression of established tumours, and reduced survival. MOR-immunoreactivity (ir) was observed in larger but not in smaller tumours. Morphine treatment resulted in increased tumour angiogenesis, peri-tumoural lymphangiogenesis, mast cell activation, and higher levels of cytokines and SP in tumours. SP-ir co-localized with mast cells and elsewhere in the tumours.
Morphine does not affect the onset of tumour development, but it promotes growth of existing tumours, and reduces overall survival in mice. MOR may be associated with morphine-induced cancer progression, resulting in shorter survival. Mast cell activation by morphine may contribute to increased cytokine and SP levels, leading to cancer progression and refractory pain.
PMCID: PMC4111281  PMID: 24861561
analgesics, opioid, morphine; angiogenesis, lymphangiogenesis; cancer; mast cells; μ-opioid receptor
25.  Association between neuraxial analgesia, cancer progression, and mortality after radical prostatectomy: a large, retrospective matched cohort study 
BJA: British Journal of Anaesthesia  2013;113(Suppl 1):i95-i102.
Systemic opioids are immunosuppressive, which could promote tumour recurrence. We, therefore, test the hypothesis that supplementing general anaesthesia with neuraxial analgesia improves long-term oncological outcomes in patients having radical prostatectomy for adenocarcinoma.
Patients who had general anaesthesia with neuraxial analgesia (n=1642) were matched 1:1 based on age, surgical year, pathological stage, Gleason scores, and presence of lymph node disease with those who had general anaesthesia only. Medical records were reviewed. Outcomes of interest were systemic cancer progression, recurrence, prostate cancer mortality, and all-cause mortality. Data were analysed using stratified proportional hazards regression, the Kaplan–Meier method, and log-rank tests. The median follow-up was 9 yr.
After adjusting for comorbidities, positive surgical margins, and adjuvant hormonal and radiation therapies within 90 postoperative days, general anaesthesia only was associated with increased risk for systemic progression [hazard ratio (HR)=2.81, 95% confidence interval (CI) 1.31–6.05; P=0.008] and higher overall mortality (HR=1.32, 95% CI 1.00–1.74; P=0.047). Although not statistically significant, similar findings were observed for the outcome of prostate cancer deaths (adjusted HR=2.2, 95% CI 0.88–5.60; P=0.091).
This large retrospective analysis suggests a possible beneficial effect of regional anaesthetic techniques on oncological outcomes after prostate surgery for cancer; however, these findings need to be confirmed (or refuted) in randomized trials.
PMCID: PMC4164176  PMID: 24346021
anaesthesia, general; analgesia, epidural, spinal; cancer progression; neoplasm metastasis; prostatectomy; prostatic neoplasms

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