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1.  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.
Background
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.
Methods
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 At each target concentration, two or three venous blood samples were withdrawn during infusion, with a further sample after the infusion ended.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.
Results
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.
Conclusions
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
doi:10.1093/bja/aem063
PMCID: PMC3838936  PMID: 17389691
anaesthetics; i.v.; ketamine; pharmacokinetics
2.  Mechanical and cold hypersensitivity in nerve-injured C57BL/6J mice is not associated with fear-avoidance- and depression-related behaviour 
British journal of anaesthesia  2007;98(6):816-822.
Background
Neuropathic pain is associated with significant co-morbidity, including anxiety and depression, which impact considerably on the overall patient experience. However, pain co-morbidity symptoms are rarely assessed in animal models of neuropathic pain. To improve the clinical validity of a widely used rodent model of traumatic peripheral neuropathy, we have investigated fear-avoidance- and depression-related behaviours in nerve-injured and sham-operated mice over a 4 week period.
Methods
Male C57BL/6J mice were subjected to partial sciatic nerve ligation (PSNL) or sham surgery and were assessed on days 7, 14, and 28 after operation. Withdrawal thresholds to punctate mechanical and cooling stimuli were measured. Mice were tested on the novel open-field and elevated plus-maze tests for fear-avoidance behaviour, and on the tail suspension test for depression-related behaviour.
Results
Hypersensitivity to punctate mechanical and cool stimuli was evident up to day 28 after PSNL. However, there was no change in fear-avoidance- or depression-related behaviours regardless of interval after-surgery.
Conclusion
These data demonstrate that pain behaviour in nerve-injured C57BL/6J mice was not associated with alterations in emotion-related behaviours.
doi:10.1093/bja/aem087
PMCID: PMC2656645  PMID: 17478455
mouse; pain, chronic; pain, neuropathic; pain, psychological variables; research, animal
3.  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
4.  The use of a stimulating catheter for total knee replacement surgery - preliminary results 
British journal of anaesthesia  2005;95(2):250-254.
Summary
Background
There is continuing debate as to whether the use of electrical stimulation that aids in localizing nerves is also beneficial for optimizing placement of nerve catheters and will lead to improved clinical outcomes such as reductions in pain scores and opioid consumption.
Methods
We undertook a retrospective, non-randomized comparison of stimulating and non-stimulating nerve catheters in 419 patients undergoing total knee replacement between December 2002 and July 2004. Pre-operatively, patients received sciatic and femoral nerve blocks, with a catheter for the femoral nerve. In 159 patients, a stimulating (Stimucath, Arrow International, Reading, PA) and, in 260 patients, a non-stimulating (Contiplex, BBraun, Melsungen, Germany) catheter system was used. Postoperatively, pain scores and morphine consumption were recorded at 4-hour intervals until the first postoperative morning. In a subset of 85 patients, the postoperative evaluation period was lengthened to three days.
Results
Post-operative visual analogue scores (VAS) for pain were similar in the two groups during the first 24 hours (P = 0.305). In patients followed for three days, VAS scores did not differ on any of the days (P = 0.427). Total morphine consumption did not differ on the first post-operative day (Stimulating: 12.4 [10.1-14.7] vs. non-stimulating: 10.4 [8.9-11.8]; mean [95% CI]; P=0.140) or on subsequent days.
Conclusions
The practical advantages of the stimulating catheter, as by reported by previous investigators, were not obvious in this clinical situation. In terms of outcome measures such as pain scores and morphine consumption, we found no significant differences between stimulating and non-stimulating catheters.
doi:10.1093/bja/aei161
PMCID: PMC1770892  PMID: 15923268
Continuous femoral nerve block; stimulating catheters; total knee replacement
5.  Ondansetron Does Not Reduce the Shivering Threshold in Healthy Volunteers 
British journal of anaesthesia  2006;96(6):732-737.
Summary
Background
Ondansetron, a serotonin-3 receptor antagonist, reduces postoperative shivering. Drugs that reduce shivering usually impair central thermoregulatory control and may thus be useful for preventing shivering during induction of therapeutic hypothermia. We determined, therefore, whether ondansetron reduces the major autonomic thermoregulatory response thresholds (trigging core temperatures) in humans.
Methods
Ten healthy volunteers were studied on two days: Control and Ondansetron (intravenous infusion to plasma concentrations of 278 (57) ng mL−1, 234 (55) ng mL−1, and 243 (58) ng mL−1at the sweating, vasoconstriction, and shivering thresholds, respectively); this corresponded to ≈50 mg of ondansetron which is roughly ten times the dose used for postoperative nausea and vomiting. Each day, skin and core temperatures were increased to provoke sweating, then reduced to elicit peripheral vasoconstriction and shivering. We determined the core-temperature sweating, vasoconstriction, and shivering thresholds after compensating for changes in mean-skin temperature. Data were analyzed with paired t tests and presented as means (SD)s; P<0.05 was statistically significant.
Results
Ondansetron did not change the sweating (Control: 37.4 (0.4)°C, Ondansetron: 37.6 (0.3)°C, P=0.16), vasoconstriction (37.0 (0.5) vs. 37.1 (0.3)°C; P=0.70), or shivering threshold (36.3 (0.5) vs. 36.3 (0.6)°C; P=0.76). No sedation was observed on either study day.
Conclusions
Ondansetron, therefore, appears to have little potential for facilitating induction of therapeutic hypothermia.
doi:10.1093/bja/ael101
PMCID: PMC1502385  PMID: 16675509
Thermoregulation; ondansetron; therapeutic hypothermia
6.  Tissue Oxygenation Response to Mild Hypercapnia during Cardiopulmonary Bypass with Constant Pump Output 
British journal of anaesthesia  2006;96(6):708-714.
Background
Tissue oxygenation is the primary determinant of wound infection risk. Mild hypercapnia markedly improves cutaneous, subcutaneous, and muscular tissue oxygenation in volunteers and patients. However, relative contributions of increased cardiac output and peripheral vasodilation to this response remains unknown. We thus tested the hypothesis that increased cardiac output is the dominant mechanism.
Methods
We recruited 10 ASA III patients, aged 40–65 years, undergoing cardiopulmonary bypass for this crossover trial. After induction of anaesthesia, a Silastic tonometer was inserted subcutaneously in the upper arm. Subcutaneous tissue oxygen tension was measured with both polarographic electrode and fluorescence-based systems. Oximeter probes were placed bilaterally on the forehead to monitor cerebral oxygenation. After initiation of cardiopulmonary bypass, in random order patients were exposed to two arterial CO2 partial pressures for 30 minutes each: 35 (normocapnia) or 50 mmHg (hypercapnia). Bypass pump flow was kept constant throughout the measurement periods.
Results
Hypercapnia during bypass had essentially no effect on PaO2, mean arterial pressure, or tissue temperature. PaCO2 and pH differed significantly. Subcutaneous tissue oxygenation was virtually identical during the two PaCO2 periods (139 [50,163] vs. 145 [38,158], P=0.335) (median [range]). In contrast, cerebral oxygen saturation (our positive control measurement) was significantly less during normocapnia (57 [28,67]%) than hypercapnia (64 [37,89]%, P=0.025).
Conclusions
Mild hypercapnia, which normally markedly increases tissue oxygenation, did not do so during cardiopulmonary bypass with fixed pump output. This suggests that hypercapnia normally increases tissue oxygenation by increasing cardiac output rather than direct dilation of peripheral vessels.
doi:10.1093/bja/ael093
PMCID: PMC1464052  PMID: 16675511
Carbon Dioxide; Hypercapnia; Hypercarbia; Acidosis; Respiratory; Oxygenation; Oxygen; Tissue; Cutaneous; Subcutaneous; Cerebral; Perfusion; Cerebrovascular; Cardiac Output
7.  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.
Summary
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.
doi:10.1093/bja/aei086
PMCID: PMC1362957  PMID: 15708868
baroreceptor reflex; clonidine; hypothermia; positive end-expiratory pressure (PEEP); thermoregulation
8.  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.
doi:10.1093/bja/aeh192
PMCID: PMC1361808  PMID: 15220178
Afferentation theory; Brainstem auditory evoked potentials; Chloroprocaine; Deafferentation; Epidural anaesthesia; Sedation; Sensory block
9.  Magnesium Sulfate Only Slightly Reduces the Shivering Threshold in Humans 
British journal of anaesthesia  2005;94(6):756-762.
Background: Hypothermia may be an effective treatment for stroke or acute myocardial infarction; however, it provokes vigorous shivering, which causes potentially dangerous hemodynamic responses and prevents further hypothermia. Magnesium is an attractive antishivering agent because it is used for treatment of postoperative shivering and provides protection against ischemic injury in animal models. We tested the hypothesis that magnesium reduces the threshold (triggering core temperature) and gain of shivering without substantial sedation or muscle weakness.
Methods: We studied nine healthy male volunteers (18-40 yr) on two randomly assigned treatment days: 1) Control and 2) Magnesium (80 mg·kg-1 followed by infusion at 2 g·h-1). Lactated Ringer's solution (4°C) was infused via a central venous catheter over a period of approximately 2 hours to decrease tympanic membrane temperature ≈1.5°C·h-1. A significant and persistent increase in oxygen consumption identified the threshold. The gain of shivering was determined by the slope of oxygen consumption vs. core temperature regression. Sedation was evaluated using verbal rating score (VRS, 0-10) and bispectral index of the EEG (BIS). Peripheral muscle strength was evaluated using dynamometry and spirometry. Data were analyzed using repeated-measures ANOVA; P<0.05 was statistically significant.
Results: Magnesium reduced the shivering threshold (36.3±0.4 [mean±SD] vs. 36.6±0.3°C, P=0.040). It did not affect the gain of shivering (Control: 437±289, Magnesium: 573±370 ml·min-1·°C-1, P=0.344). The magnesium bolus did not produce significant sedation or appreciably reduce muscle strength.
Conclusions: Magnesium significantly reduced the shivering threshold; however, due to the modest absolute reduction, this finding is considered to be clinically unimportant for induction of therapeutic hypothermia.
doi:10.1093/bja/aei105
PMCID: PMC1361806  PMID: 15749735
Magnesium; Temperature; Thermoregulation; Therapeutic hypothermia; Brain protection; Cardiac protection; Shivering
10.  Supplemental Oxygen Does Not Reduce Postoperative Nausea and Vomiting after Thyroidectomy 
British journal of anaesthesia  2003;91(6):857-861.
Summary
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
11.  The Intubating Laryngeal Mask Airway Allows Tracheal Intubation When the Cervical Spine Is Immobilized by a Rigid Collar 
British journal of anaesthesia  2004;93(5):655-659.
Summary
An intubating laryngeal mask airway (ILMA) facilitates tracheal intubation with the neck in neutral position, which is similar to the neck position maintained by a rigid cervical collar. However, a cervical collar virtually obliterates neck movement, even the small movements that normally facilitate airway insertion. We therefore tested the hypothesis that the ILMA facilitates tracheal intubation even in patients wearing a rigid cervical collar. In 50 cervical spine surgery patients with a rigid Philadelphia collar in place and 50 general surgery patients under general anaesthesia, we performed blind tracheal intubation via an ILMA. The time required for intubation, intubation success rate, and numbers and type of adjusting manoeuvres employed were recorded. Inter-incisor distance was significantly smaller (4.1 [0.8] cm vs. 4.6 [0.7] cm, mean [SD], P<0.01) and Mallampati scores were significantly greater (P<0.001) in the collared patients. ILMA insertion took longer (30 [25] vs. 22 [6] seconds), more patients required 2 insertion attempts (15 vs. 3; P<0.005), and ventilation adequacy with ILMA was worse (P<0.05) in collared patients. However, there were no significant differences between the collared and control patients in terms of total time required for intubation (60 [41] vs. 50 [30] seconds), number of intubation attempts, overall intubation success rate (96 vs. 98%), or the incidence of intubation complications. Blind intubation through an ILMA is thus a reasonable strategy for controlling the airway in patients who are immobilized with a rigid cervical collar, especially when urgency precludes a fiberoptic approach.
doi:10.1093/bja/aeh248
PMCID: PMC1283102  PMID: 15321932
anaesthesia; intubation; tracheal; laryngeal mask; cervical collar

Results 1-11 (11)