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1.  Advances in understanding the mechanisms and management of persistent pain in older adults† 
British journal of anaesthesia  2008;101(1):111-120.
Older adults with persistent pain are not simply a chronologically older version of younger pain patients. Pain-related disability in older adults may be driven by pain ‘homeostenosis’, that is, diminished ability to effectively respond to the stress of persistent pain. Some of the comorbidities of ageing that can contribute to pain homeostenosis include cognitive and physical impairments, increased sensitivity to suprathreshold pain stimuli, medical and psychological comorbidities, altered pharmacokinetics and pharmacodynamics, and social isolation. A key distinction between older and younger individuals with persistent pain is the normal and pathological ageing-associated brain changes. These may alter the expression and experience of pain with impaired descending inhibition and dysfunction of pain gating mechanisms. Cognizance of these brain changes is needed to guide appropriate evaluation and treatment approaches. This paper reviews data that support these ageing-associated phenomena. Specifically, we discuss age-related changes in the brain (both normal and pathological) and in pain physiology; changes in experience and expression of pain that occur with dementia and contribute to pain homeostenosis; and unique aspects of age and pain-associated psychological function and their contribution to disability. We also present data demonstrating changes in brain morphology and neuropsychological performance that accompany persistent non-malignant pain in older adults and the treatment implications of these brain changes. Finally, preliminary data are presented on the efficacy of mindfulness meditation, a treatment that has been examined explicitly in older adults and targets optimizing brain function and descending inhibition.
doi:10.1093/bja/aen090
PMCID: PMC2841779  PMID: 18487247
age factors; pain; chronic; stress
2.  Onset and effectiveness of rocuronium for rapid onset of paralysis in patients with major burns: priming or large bolus 
Background
Burn injury leads to resistance to the effects of non-depolarizing muscle relaxants. We tested the hypothesis that a larger bolus dose is as effective as priming for rapid onset of paralysis after burns.
Methods
Ninety adults, aged 18–59 yr with 40 (2)% [mean (se)] burn and 30 (2) days after injury, received rocuronium as a priming dose followed by bolus (0.06+0.94 mg kg−1), or single bolus of either 1.0 or 1.5 mg kg−1. Sixty-one non-burned, receiving 1.0 mg kg−1 as a primed (0.06+0.94 mg kg−1) or full bolus dose, served as controls. Acceleromyography measured the onset times.
Results
Priming when compared with 1.0 mg kg−1 bolus in burned patients shortened the time to first appearance of twitch depression (30 vs 45 s, P<0.05) and time to maximum twitch inhibition (135 vs 210 s, P<0.05). The onset times between priming and higher bolus dose (1.5 mg kg−1) were not different (30 vs 30 s for first twitch depression and 135 vs 135 s for maximal depression, respectively). The onset times in controls, however, were significantly (P<0.05) faster than burns both for priming and for full bolus (15 and 15 s, respectively, for first twitch depression and 75 and 75 s for maximal depression). Priming caused respiratory distress in 10% of patients in both groups. Intubating conditions in burns were significantly better with 1.5 mg kg−1 than with priming or full 1.0 mg kg−1 bolus.
Conclusions
A dose of 1.5 mg kg−1 not only produces an initial onset of paralysis as early as 30 s, which we speculate could be a reasonable onset time for relief of laryngospasm, but also has an onset as fast as priming with superior intubating conditions and no respiratory side-effects.
doi:10.1093/bja/aen332
PMCID: PMC2638834  PMID: 19029093
burns; neuromuscular block, rocuronium
3.  Morphine pharmacokinetics and pharmacodynamics in preterm and term neonates: secondary results from the NEOPAIN trial 
BJA: British Journal of Anaesthesia  2008;101(5):680-689.
Background
Relationships between plasma morphine concentrations and neonatal responses to endotracheal tube (ETT) suctioning are unknown in preterm neonates.
Methods
Ventilated preterm neonates (n=898) from 16 centres were randomly assigned to placebo (n=449) or morphine (n=449). After an i.v. loading dose (100 µg kg−1), morphine infusions [23–26 weeks postmenstrual age (PMA) 10 µg kg−1 h−1; 27–29 weeks 20 µg kg−1 h−1; and 30–32 weeks 30 µg kg−1 h−1] were established for a maximum of 14 days. Open-label morphine (20–100 µg kg−1) was given for pain or agitation. Morphine assay and neonatal response to ETT suctioning was measured at 20–28 and 70–76 h after starting the drug infusion and at 10–14 h after discontinuation of the study drug. The concentration–effect response was investigated using non-linear mixed effects models.
Results
A total of 5119 data points (1598 measured morphine concentrations and 3521 effect measures) were available from 875 neonates for analysis. Clearance was 50% that of the mature value at 54.2 weeks PMA (CLmat50) and increased from 2.05 litre h−1 70 kg−1 at 24 weeks PMA to 6.04 litre h−1 70 kg−1 at 32 weeks PMA. The volume of distribution in preterm neonates was 190 litre 70 kg−1 (CV 51%) and did not change with age. There was no relationship between morphine concentrations (range 0–440 µg litre−1) and heart rate changes associated with ETT suctioning or with the Premature Infant Pain Profile.
Conclusions
A sigmoid curve describing maturation of morphine clearance is moved to the right in preterm neonates and volume of distribution is increased compared with term neonates. Morphine does not alter the neonatal response to ETT suctioning.
doi:10.1093/bja/aen248
PMCID: PMC2733178  PMID: 18723857
anaesthesia, paediatric; anaesthetic–analgesic regimens; analgesics opioid, morphine; model, pharmacodynamic; model, pharmacokinetic
4.  Variation of bispectral index under TIVA with propofol in a paediatric population 
Background
In this prospective observational study, we aim to explore the relationship between age and BIS values at different plasma concentrations of propofol.
Methods
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).
Results
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.
Conclusions
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.
doi:10.1093/bja/aem339
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
5.  Facial muscle activity, Response Entropy, and State Entropy indices during noxious stimuli in propofol–nitrous oxide or propofol–nitrous oxide–remifentanil anaesthesia without neuromuscular block 
BJA: British Journal of Anaesthesia  2008;102(2):227-233.
Background
Entropy™ is an anaesthetic EEG monitoring method, calculating two numerical parameters: State Entropy (SE, range 0–91) and Response Entropy (RE, range 0–100). Low Entropy numbers indicate unconsciousness. SE uses the frequency range 0.8–32 Hz, representing predominantly the EEG activity. RE is calculated at 0.8–47 Hz, consisting of both EEG and facial EMG. RE–SE difference (RE−SE) can indicate EMG, reflecting nociception. We studied RE−SE and EMG in patients anaesthetized without neuromuscular blockers.
Methods
Thirty-one women were studied in propofol–nitrous oxide (P) or propofol–nitrous oxide–remifentanil (PR) anaesthesia. Target SE value was 40–60. RE−SE was measured before and after endotracheal intubation, and before and after the commencement of surgery. The spectral content of the signal was analysed off-line. Appearance of EMG on EEG was verified visually.
Results
RE, SE, and RE−SE increased during intubation in both groups. Elevated RE was followed by increased SE values in most cases. In these patients, spectral analysis of the signal revealed increased activity starting from low (<20 Hz) frequency area up to the highest measured frequencies. This was associated with appearance of EMG in raw signal. No spectral alterations or EMG were seen in patients with stable Entropy values.
Conclusions
Increased RE is followed by increased SE at nociceptive stimuli in patients not receiving neuromuscular blockers. Owing to their overlapping power spectra, the contribution of EMG and EEG cannot be accurately separated with frequency analysis in the range of 10–40 Hz.
doi:10.1093/bja/aen356
PMCID: PMC2638861  PMID: 19112059
anaesthetics i.v., propofol; analgesics opioid, remifentanil; measurement techniques, electromyography; monitoring, electroencephalography
6.  Effect of haemodilution, acidosis, and hypothermia on the activity of recombinant factor VIIa (NovoSeven®) 
BJA: British Journal of Anaesthesia  2008;101(3):324-331.
Background
A range of plasma volume expanders is used clinically, often in settings where haemostasis may already be impaired. The haemostatic agent, recombinant activated factor VII (rFVIIa, NovoSeven®), may be used to improve haemostasis but potential interactions with different volume expanders are poorly understood.
Methods
Clot formation was measured by thromboelastography (TEG) using blood from healthy volunteers. In vitro effects of rFVIIa with haemodilution, acidosis, and hypothermia were examined. Conditions were induced by dilution with NaCl (0.9%), lactated Ringer's solution, albumin 5%, or hydroxyethyl starch (HES) solutions [MW (molecular weight) 130–670 kDa]; by adjusting pH to 6.8 with 1 M HEPES (N-2-hydroxyethylpiperazine-N′-2-ethanesulphonic acid) buffer; or by reducing temperature to 32°C. We also studied the effect of low vs high MW HES (MW 200 vs 600 kDa) and rFVIIa on in vivo bleeding time (BT) in rabbits.
Results
Haemodilution progressively altered TEG parameters. rFVIIa improved TEG parameters in the presence of acidosis, hypothermia or 20% haemodilution (P<0.05). At 40% haemodilution, the rFVIIa effect was diminished particularly with high MW HES. In vivo, rFVIIa shortened the BT (P<0.05) with low but not high MW HES.
Conclusions
Efficacy of rFVIIa was affected by the degree of haemodilution and type of volume expander, but not by acidosis or hypothermia.
doi:10.1093/bja/aen175
PMCID: PMC2517151  PMID: 18565966
blood, haemodilution; complications, acidosis; hypothermia; measurement techniques, thromboelastography; rFVIIa; surgery, haemostatic response
7.  Contamination of salvaged maternal blood by amniotic fluid and fetal red cells during elective Caesarean section 
BJA: British Journal of Anaesthesia  2008;101(2):225-229.
Background
Cell salvage in obstetrics is still a controversial subject and has yet to be fully embraced. The aim of this exploratory study was to measure amniotic fluid (AF), heparin, and fetal red cell contamination of washed filtered salvaged maternal blood and to investigate differences based on the number of suction devices used.
Methods
Patients undergoing elective Caesarean section were assigned alternately to one of two groups. In Group 1, all blood and AF was collected with one suction. In Group 2, AF was aspirated to waste with a second separate suction device before collection of any blood.
Results
In both groups, alpha-fetoprotein (AFP), squames cells, and heparin were significantly reduced (P<0.001) by the washing and filtering process. Mean AFP levels post-filtration were 2.58 IU ml−1 in Group 1 and 3.53 IU ml−1 in Group 2. Squames cells were completely removed in all but two cases. Fetal red blood cells were still present in the final product, range 0.13–4.35%. In Group 1, haemoglobin and haematocrit were higher than in Group 2, with lower white blood cell, AFP, and fetal red cell counts.
Conclusions
This study adds to the growing body of evidence that there is little or no possibility for AF contamination to enter the re-infusion system when used in conjunction with a leucodepletion filter.
doi:10.1093/bja/aen135
PMCID: PMC2447531  PMID: 18515817
blood, salvage; equipment, cell saver; transfusion, autotransfusion

Results 1-7 (7)