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 At each target concentration, two or three venous blood samples were withdrawn during infusion, with a further sample after the infusion ended.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
anaesthetics; i.v.; ketamine; pharmacokinetics
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.
age factors; pain; chronic; stress
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.
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
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.
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.
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.
These data demonstrate that pain behaviour in nerve-injured C57BL/6J mice was not associated with alterations in emotion-related behaviours.
mouse; pain, chronic; pain, neuropathic; pain, psychological variables; research, animal
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.
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.
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.
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.
Continuous femoral nerve block; stimulating catheters; total knee replacement
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.
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.
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.
Ondansetron, therefore, appears to have little potential for facilitating induction of therapeutic hypothermia.
Thermoregulation; ondansetron; therapeutic hypothermia
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.
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.
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).
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.
Carbon Dioxide; Hypercapnia; Hypercarbia; Acidosis; Respiratory; Oxygenation; Oxygen; Tissue; Cutaneous; Subcutaneous; Cerebral; Perfusion; Cerebrovascular; Cardiac Output
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.
baroreceptor reflex; clonidine; hypothermia; positive end-expiratory pressure (PEEP); thermoregulation
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.
Afferentation theory; Brainstem auditory evoked potentials; Chloroprocaine; Deafferentation; Epidural anaesthesia; Sedation; Sensory block
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.
Magnesium; Temperature; Thermoregulation; Therapeutic hypothermia; Brain protection; Cardiac protection; Shivering
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.
Anaesthesia; droperidol; oxygen; postoperative complications: nausea and vomiting; surgery: thyroidectomy
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  vs. 22  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  vs. 50  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.
anaesthesia; intubation; tracheal; laryngeal mask; cervical collar
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.
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
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.
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