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Background: Malignant Hyperthermia (MH) is a life-threatening reaction triggered by volatile anaesthetics and succinylcholine characterized by hypercapnia, hypermetabolism and muscle breakdown. MH is most commonly caused by mutations in the skeletal muscle ryanodine receptor (RYR1) gene, as is rhabdomyolysis triggered by exertion and/or pyrexia. The discrepancy between risk genotypes and actual MH incidence remains unexplained. We hypothesized that MH is a compound event, reflecting a synergistic effect of predisposing genotype, triggering anaesthetic, and exercise and/or pyrexia as modifying factors. Methods: We performed a retrospective study and identified 41 patients with a history of exercise and/or pyrexia within 72 hours prior to an MH event. We compared the frequency of a history of exercise and/or pyrexia within 72 hours of the triggering agent in “eventful anaesthesias” (n=41) and in “uneventful anaesthesias” (n=51) in the index cases and/or their MH susceptible relatives. Indications for and urgency of surgery, and use of succinylcholine were also recorded. Findings: In eventful anaesthesias, there was a history of exercise and/or pyrexia within 72 hours prior to the anaesthetic in 24(0) and 21(1) patients, compared to 0 and 1 in uneventful anesthesias. Trauma and acute abdomen as surgery indications, emergency surgery and succinylcholine use were also more common with eventful anaesthesias. Interpretation: Exercise and/or pyrexia prior to general anaesthesia are risk factors for MH. Rhabdomyolysis may mimic an acute abdomen, whilst trauma surgery may carry a specific risk due to muscle damage. These observations should inform perioperative guidelines with the potential to reduce fatal anaesthesia complications. Funding Statement: This work is not funded. Declaration of Interests: Sheila Riazi, Luuk van den Bersselaar, Gunilla Islander, Luc Heytens, Marc M. J. Snoeck, Andrew Bjorksten, Robyn Gillies, George Dranitsaris, Anna Hellblom, Susan Treves, Nicol C. Voermans, Heinz Jungbluth: These authors declare no financial interests. Ethics Approval Statement: The retrospective case study was performed with Research Ethics Board approval from the University of Toronto (REB Nr 19-5365), and in accordance with the ethics guidelines issued by other participating centres.

Summary Adrenomedullary chromaffin cells are catecholamine (CA)-producing cells originating from trunk neural crest (NC) via sympathoadrenal progenitors (SAPs). We generated NC and SAPs from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) in vitro via BMP2/FGF2 exposure, ascertained by qPCR and immunoexpression of SOX10, ASCL1, TFAP2α, and PHOX2B, and by fluorescence-activated cell sorting selection for p75NTR and GD2, and confirmed their trunk-like HOX gene expression. We showed that continuing BMP4 and curtailing FGF2 in vitro, augmented with corticosteroid mimetic, induced these cells to upregulate the chromaffin cell-specific marker PNMT and other CA synthesis and storage markers, and we demonstrated noradrenaline and adrenaline by Faglu and high-performance liquid chromatography. We showed these human cells' SAP-like property of migration and differentiation into cells expressing chromaffin cell markers by implanting them into avian embryos in vivo and in chorio-allantoic membrane grafts. These cells have the potential for investigating differentiation of human chromaffin cells and for modeling diseases involving this cell type., Highlights • Human ESCs and iPSCs differentiated to chromaffin cells via sympathoadrenal stage • Chromaffin-like cells are identified by PNMT expression • Adrenaline and noradrenaline production is revealed by FAGLU and by HPLC • Selection of GD2+ sympathoadrenal cells improves chromaffin cell differentiation, In this article, Newgreen and colleagues show that human pluripotent cells can be induced to form chromaffin-like cells, which produce adrenaline and noradrenaline in vitro. The method uses the dual-inhibitor method to induce neural crest progenitor and sympathoadrenal-like cells then extended BMP4 and corticosteroid exposure for the chromaffin-like stage, with curtailed FGF2 exposure to limit sympathetic neuron induction.

Background Central core disease and malignant hyperthermia are human disorders of skeletal muscle resulting from aberrant Ca2+ handling. Most malignant hyperthermia and central core disease cases are associated with amino acid changes in the type 1 ryanodine receptor (RyR1), the skeletal muscle Ca2+-release channel. Malignant hyperthermia exhibits a gain-of-function phenotype, and central core disease results from loss of channel function. For a variant to be classified as pathogenic, functional studies must demonstrate a correlation with the pathophysiology of malignant hyperthermia or central core disease. Objective We assessed the pathogenicity of four C-terminal variants of the ryanodine receptor using functional analysis. The variants were identified in families affected by either malignant hyperthermia or central core disease. Methods Four variants were introduced separately into human cDNA encoding the skeletal muscle ryanodine receptor. Following transient expression in HEK-293T cells, functional studies were carried out using calcium release assays in response to an agonist. Two previously characterized variants and wild-type skeletal muscle ryanodine receptor were used as controls. Results The p.Met4640Ile variant associated with central core disease showed no difference in calcium release compared to wild-type. The p.Val4849Ile variant associated with malignant hyperthermia was more sensitive to agonist than wild-type but did not reach statistical significance and two variants (p.Phe4857Ser and p.Asp4918Asn) associated with central core disease were completely inactive. Conclusions The p.Val4849Ile variant should be considered a risk factor for malignant hyperthermia, while the p.Phe4857Ser and p.Asp4918Asn variants should be classified as pathogenic for central core disease.

To examine the impact of glutamate on post-operative seizures and survival in a cohort of patients with grade II to IV supratentorial glioma. A retrospective analysis was performed on 216 patients who underwent surgery for supratentorial gliomas. Primary explanatory variables were peritumoural and/or tumoural glutamate concentrations, glutamate transporter expression (EAAT2 and SXC). Univariate and multivariate survival analysis was performed with primary outcomes of time to first post-operative seizure and overall survival. Subgroup analysis was performed in patients with de novo glioblastomas who received adjuvant chemoradiotherapy. 47 (21.8 %), 34 (15.8 %) and 135 (62.5 %) WHO grade II, III and IV gliomas respectively were followed for a median of 15.8 months. Following multivariate analysis, there was a non-significant association between higher peritumoural glutamate concentrations and time to first post-operative seizure (HR 2.07, CI 0.98-4.37, p = 0.06). In subgroup analysis of 81 glioblastoma patients who received adjunct chemoradiotherapy, peritumoural glutamate concentration was significantly associated with time to first post-operative seizure (HR 3.10, CI 1.20-7.97, p = 0.02). In both the overall cohort and subgroup analysis no glutamate cycle biomarkers were predictive of overall survival. Increased concentrations of peritumoural glutamate were significantly associated with shorter periods of post-operative seizure freedom in patients with de novo glioblastomas treated with adjuvant chemoradiotherapy. No glutamate cycle biomarkers were predictive of overall survival. These results suggest that therapies targeting glutamate may be beneficial in tumour associated epilepsy.

Summary Background Infant spinal anesthesia with levobupivacaine has been promoted as a technique to reduce both the risk of postoperative apnea and exposure to volatile anesthesia. There is, however, no pharmacokinetic data to support the currently recommended doses. Aims Our aim was to determine whether infant levobupivacaine spinal anesthesia is associated with plasma concentrations consistent with a low risk of local anesthetic systemic toxicity. Methods This was an open-label pharmacokinetic safety and tolerability study of levobupivacaine spinal anesthesia in infants

Significance In human muscle with ryanodine receptor (RyR) variants, there is expected to be a change in the basal RyRs Ca 2+ leak that may alter local Ca 2+ dynamics. It is not currently possible to assess these basal Ca 2+ dynamics in human muscle. By trapping a Ca 2+ -sensitive fluorescent dye in the transverse tubular (t)-system of freshly biopsied human skeletal muscle fibers we could detect tiny local RyR-dependent Ca 2+ movements. We show that malignant hyperthermia (MH) causative RyR variant human muscle displays a chronically different RyR Ca 2+ leak which reconfigures the Ca 2+ -handling properties by the t-system. This approach can be used to assess human muscle for function and pathogenicity of other RyR variants of uncertain significance, MH susceptibility, and assessment of drugs targeted to the Ca 2+ -handling proteins.

Glioma cells release glutamate through expression of system xc-, which exchanges intracellular glutamate for extracellular cysteine. Lack of the excitatory amino acid transporter 2 (EAAT2) expression maintains high extracellular glutamate levels in the glioma microenvironment, causing excitotoxicity to surrounding parenchyma. Not only does this contribute to the survival and proliferation of glioma cells, but is involved in the pathophysiology of tumour-associated epilepsy (TAE). We investigated the role of the peroxisome proliferator activated receptor gamma (PPARγ) agonist pioglitazone in modulating EAAT2 expression in glioma cells. We found that EAAT2 expression was increased in a dose dependent manner in both U87MG and U251MG glioma cells. Extracellular glutamate levels were reduced with the addition of pioglitazone, where statistical significance was reached in both U87MG and U251MG cells at a concentration of ≥ 30 μM pioglitazone (p < 0.05). The PPARγ antagonist GW9662 inhibited the effect of pioglitazone on extracellular glutamate levels, indicating PPARγ dependence. In addition, pioglitazone significantly reduced cell viability of U87MG and U251MG cells at ≥ 30 μM and 100 μM (p < 0.05) respectively. GW9662 also significantly reduced viability of U87MG and U251MG cells with 10 μM and 30 μM (p < 0.05) respectively. The effect on viability was partially dependent on PPARγ activation in U87MG cells but not U251MG cells, whereby PPARγ blockade with GW9662 had a synergistic effect. We conclude that PPARγ agonists may be therapeutically beneficial in the treatment of gliomas and furthermore suggest a novel role for these agents in the treatment of tumour associated seizures through the reduction in extracellular glutamate.

Defects in the genes coding for the skeletal muscle ryanodine receptor (RYR1) and alpha 1 subunit of the dihydropyridine receptor (CACNA1S) have been identified as causative for malignant hyperthermia (MH). Sixty-two MH susceptible individuals presenting to the same diagnostic centre had copy deoxyribonucleic acid, derived from muscle ribonucleic acid, sequenced to identify variants with the potential to be responsible for the MH phenotype in both RYR1 and CACNA1S. These genetic findings were combined with clinical episode details and in vitro contracture test results to improve our understanding of the Australian MH cohort. Twelve novel variants were identified in RYR1 and six in CACNA1S. Known RYR1 causative mutations were identified in six persons and novel variants in RYR1 and CACNA1S in a further 17 persons. Trends indicated higher mutation identification in those with more definitive clinical episodes and stronger in vitro contracture test responses.

Neurons release neurotransmitters such as glutamate to communicate with each other and to coordinate brain functioning. As increased glutamate release is indicative of neuronal maturation and activity, a system that can measure glutamate levels over time within the same tissue and/or culture system is highly advantageous for neurodevelopmental investigation. To address such challenges, we develop for the first time a convenient method to realize functionalized borosilicate glass capillaries with nanostructured texture as an electrochemical biosensor to detect glutamate release from cerebral organoids generated from human embryonic stem cells (hESC) that mimic various brain regions. The biosensor shows a clear catalytic activity toward the oxidation of glutamate with a sensitivity of 93 ± 9.5 nA·µM−1·cm−2. It was found that the enzyme-modified microelectrodes can detect glutamate in a wide linear range from 5 µM to 0.5 mM with a limit of detection (LOD) down to 5.6 ± 0.2 µM. Measurements were performed within the organoids at different time points and consistent results were obtained. This data demonstrates the reliability of the biosensor as well as its usefulness in measuring glutamate levels across time within the same culture system.

This study aimed to evaluate and validate chemical shift imaging (CSI) for in vivo glutamate (Glu) quantification in patients with supratentorial gliomas. If validated, CSI could become an extremely useful tool to investigate metabolic dysfunction of Glu in excitotoxic neuropathologies. Quantitative CSI estimates of Glu concentrations were compared with known concentrations of Glu in aqueous phantom solutions. Forty-one patients with known or likely supratentorial gliomas underwent preoperative CSI. The spectra obtained were analyzed for Glu concentrations and Glu to creatine (Cr) ratios. These in vivo measurements were correlated against ex vivo Glu content quantified by high performance liquid chromatography (HPLC) measured in 65 resected brain tumor and peritumoral brain specimens. For the phantom solutions the CSI estimates of Glu concentration and the Glu/Cr ratios were highly correlated with known Glu concentration (r² = 0.95, p = 0.002, and r² = 0.97, p

Tramadol is used in children aged

The genetic basis of malignant hyperthermia (MH) is not fully characterised and likely involves more than just the currently classified mutations in the gene encoding the skeletal muscle ryanodine receptor ( RYR1) and the gene encoding the α1 subunit of the dihydropyridine receptor ( CACNA1S). In this paper we sequence other genes involved in calcium trafficking within skeletal muscle in patients with positive in vitro contracture tests, searching for alternative genes associated with MH. We identified four rare variants in four different genes ( CACNB1, CASQ1, SERCA1 and CASQ2) encoding proteins involved in calcium handling in skeletal muscle in a cohort of 30 Australian MH susceptible probands in whom prior complete sequencing of RYR1 and CACNA1S had yielded no rare variants. These four variants have very low minor allele frequencies and while it is tempting to speculate that they have a role in MH, they remain at present variants of unknown significance. Nevertheless they provide the basis for a new set of functional studies, which may indeed identify novel players in MH.

We compared plasma and cerebrospinal fluid (CSF) pharmacokinetics of paracetamol after intravenous (IV) and oral administration to determine dosing regimens that optimize CSF concentrations.Twenty-one adult patients were assigned randomly to 1 g IV, 1 g oral or 1.5 g oral paracetamol. An IV cannula and lumbar intrathecal catheter were used to sample venous blood and CSF, respectively, over 6 hours. The plasma and CSF maximum concentrations (Cmax), times to maximum concentrations (Tmax), and area under the plasma and CSF concentration-time curves (AUCs) were calculated using noncompartmental techniques. Significance was defined by P.0167 (Bonferroni correction for 3 comparisons for each parameter). Probability (XY) (p″) with Bonferroni corrected 95% confidence intervals (CIs) were calculated (CIs including 0.5 meet the null hypothesis). Results are presented as median (range) or p″ (CI). P values are listed as 1 g IV vs 1 g orally, 1 g IV vs 1.5 g orally and 1 g orally vs 1.5 g orally, respectively.Wide variation in measured paracetamol concentrations was observed, especially in the oral groups. The median plasma Cmax in the 1 g IV group was significantly greater than the oral groups. In contrast, the median CSF Cmax was not different between groups. The median plasma Tmax in the 1 g IV group was 105 and 75 minutes earlier than in the 1 and 1.5 g oral groups. The median CSF Tmax was not significantly different between groups. The median plasma AUC (total) was not significantly different between groups; however, in the first hour, the median plasma AUC was significantly greater in the IV group than in the oral groups. In the second hour, there was no difference between groups. The median CSF AUC (total) did not significantly differ between groups; however, in the first hour, the median CSF AUC was significantly greater in the IV compared with the orally groups. In the second hour, there was no difference between groups. Our analysis indicated that the median Cmax, Tmax, and AUC values lacked precision because of small sample sizes.Peak plasma concentrations were greater and reached earlier after IV than oral dosing. Evidence for differences in CSF Cmax and Tmax was lacking because of the small size of this study.

Nineteen adult patients of either gender received intravenous infusions of propofol, scaled to estimated lean body mass (LBM), for 150 minutes as part of a balanced anaesthetic. Arterial blood was assayed for whole blood propofol. The first subject received propofol at a fixed rate of 0.058 mg.min-1.kgLBM-1. Subsequent groups received variable rate infusions based on the ratio of the infusion rate to the propofol concentration at each sampling point in the previous group, multiplied by the target concentration. After groups of one, two, five and 11 subjects, the median weighted residual was 0.040 and median absolute weighted residual was 0.153. Population pharmacokinetic analysis of the final group of six females and five males, aged 29 to 70 years and of 16.5 to 44.2% body fat, resulted in a two compartment pharmacokinetic model with coefficients and standard errors of V1=0.102 (0.0155) l/kgLBM, V2=0.257 (0.079) l/kgLBM, k10=0.423 (0.069) /min, k12=0.222 (0.051) /min, k21=0.084 (0.02) /min and clearance=0.0418 (0.0023) l.min-1.kgLBM-1. The only significant covariate was LBM. Within infusion data improved prediction when compared with data derived in previous studies from random observations.

Advances in analysis of the RYR1 gene (which encodes the skeletal muscle ryanodine receptor) show that genetic examination is a useful adjunct to the in vitro contracture test in the diagnosis of malignant hyperthermia, as defects in RYR1 have been shown to be responsible for malignant hyperthermia susceptibility. DNA from 34 malignant hyperthermia susceptible individuals and four malignant hyperthermia equivocal subjects was examined using direct sequencing of ‘hotspots’ in the RYR1 gene to identify mutations associated with malignant hyperthermia. Seven different causative mutations (as defined by the European Malignant Hyperthermia Group) in nine malignant hyperthermia susceptible individuals were identified. In another six malignant hyperthermia susceptible individuals, five different published but as yet functionally uncharacterised mutations were identified. A further three as yet unpublished and functionally uncharacterised (novel) mutations were identified in three malignant hyperthermia susceptible samples. If the novel and previously published mutations prove to be functionally associated with calcium homeostasis, then this method of analysis achieved a mutation detection rate of 47%. Based on the number of relatives presenting to our unit in the study period, the muscle biopsy rate would have decreased by 25%. That we only identified a genetic defect in RYR1 in 47% of in vitro contracture test positive individuals suggests that there are other areas in RYR1 where pathogenic mutations may occur and that RYR1 may not be the sole gene associated with malignant hyperthermia. It may also reflect a less than 100% specificity of the in vitro contracture test.

Background We tested the hypothesis that there is greater suppression of autonomic reflexes during general anaesthesia when fentanyl is administered epidurally than when it is given intravenously. Methods Ten volunteers were anaesthetized with desflurane. Noxious stimuli of variable intensity were then delivered by tetanic electrical stimuli. Heart rate, arterial pressure, and pupillary dilation in response to these stimuli defined nociception. Seven of these volunteers participated twice using a crossover design: they received i.v. fentanyl on one study day and epidurally on the other. Autonomic responses to alternative tetanic stimuli at L4 and C5 dermatomes were measured every 5 min for 3 h after fentanyl administration. Results After a brief redistribution period, plasma fentanyl concentrations were virtually identical on both days. After stimulation of the L4 dermatome only, block of pupillary reflex dilation was greater by 47 (22)% after epidural fentanyl compared with i.v. fentanyl. Time to maximal depression of reflex dilation after L4 stimulation was 41 (13) min. Arterial pressure and heart rate decreased after fentanyl by either route but there were no differences observed between L4 and C5 stimulations. Conclusion We conclude that during general anaesthesia, epidural fentanyl enhances antinociception by a spinal mechanism which can be detected by pupillary dilation but not by changes in arterial pressure or heart rate.

Reactive oxygen species (ROS) have been linked with both depressed Na(+),K(+)-pump activity and skeletal muscle fatigue. This study investigated N-acetylcysteine (NAC) effects on muscle Na(+),K(+)-pump activity and potassium (K(+)) regulation during prolonged, submaximal endurance exercise. Eight well-trained subjects participated in a double-blind, randomised, crossover design, receiving either NAC or saline (CON) intravenous infusion at 125 mg kg(-1) h(-1) for 15 min, then 25 mg kg(-1) h(-1) for 20 min prior to and throughout exercise. Subjects cycled for 45 min at 71% , then continued at 92% until fatigue. Vastus lateralis muscle biopsies were taken before exercise, at 45 min and fatigue and analysed for maximal in vitro Na(+),K(+)-pump activity (K(+)-stimulated 3-O-methyfluorescein phosphatase; 3-O-MFPase). Arterialized venous blood was sampled throughout exercise and analysed for plasma K(+) and other electrolytes. Time to fatigue at 92% was reproducible in preliminary trials (c.v. 5.6 +/- 0.6%) and was prolonged with NAC by 23.8 +/- 8.3% (NAC 6.3 +/- 0.5 versus CON 5.2 +/- 0.6 min, P < 0.05). Maximal 3-O-MFPase activity decreased from rest by 21.6 +/- 2.8% at 45 min and by 23.9 +/- 2.3% at fatigue (P < 0.05). NAC attenuated the percentage decline in maximal 3-O-MFPase activity (%Deltaactivity) at 45 min (P < 0.05) but not at fatigue. When expressed relative to work done, the %Deltaactivity-to-work ratio was attenuated by NAC at 45 min and fatigue (P < 0.005). The rise in plasma [K(+)] during exercise and the Delta[K(+)]-to-work ratio at fatigue were attenuated by NAC (P < 0.05). These results confirm that the antioxidant NAC attenuates muscle fatigue, in part via improved K(+) regulation, and point to a role for ROS in muscle fatigue.

Background The transversus abdominis plane (TAP) block involves injecting a large volume of local anaesthetic between the muscles of the abdominal wall. Plasma concentrations of ropivacaine after gynaecological laparotomy are potentially high enough to result in systemic toxicity, and there are pharmacokinetic reasons why pregnancy may increase susceptibility to local anaesthetic toxicity. Methods Adult female patients (n=30) undergoing elective Caesarean section under spinal anaesthesia received bilateral ultrasound-guided TAP blocks after wound closure (2.5 mg kg−1 of ropivacaine diluted to 40 ml). Venous blood samples were collected at 10, 20, 30, 45, 60, 90, 120, 180 and 240 min following the block. Blood samples were assayed for total and free ropivacaine concentrations. Patients were assessed for symptoms of local anaesthetic toxicity. Results The mean [standard deviation ( sd )] peak total concentration of ropivacaine occurred at 30 min post-injection and was 1.82 (0.69) μg ml−1. The maximum detected concentration in any patient was 3.76 μg ml−1 (at 10 min post-injection). Three patients reported symptoms of mild neurotoxicity, and the mean ( sd ) peak levels were elevated in these patients, 2.70 (0.46) µg ml−1. Conclusions TAP blocks can result in elevated plasma ropivacaine concentrations in patients undergoing Caesarean section, which may be associated with neurotoxicity.

Background There are few data describing levobupivacaine pharmacokinetics in infants ( Methods An open-label study was undertaken to examine the pharmacokinetics of levobupivacaine 2.5 mg ml −1 , 2 mg kg −1 in children aged less than 3 months after single-shot caudal epidural administration. Plasma concentrations were determined at intervals from 0.5 to 4 h after injection. A population pharmacokinetic analysis of levobupivacaine time–concentration profiles (84 observations) from 22 infants with mean postnatal age (PNA) 2.0 (range 0.6–2.9) months was undertaken using non-linear mixed effects models (NONMEM). Time–concentration profiles were analysed using a one-compartment model with first-order input and first-order elimination. Estimates were standardized to a 70 kg adult using allometric size models. Results Population parameter estimates (between-subject variability) for total levobupivacaine were clearance (CLt) 12.8 [coefficient of variation (CV) 50.6%] litre h −1 70 kg −1 , volume of distribution (Vt) 202 (CV 31.6%) litre 70 kg −1 , absorption half-life (Tabs) 0.323 (CV 18.6%) h 70 kg −1 . Estimates for the unbound drug were clearance (CLfree) 104 (CV 43.5%) litre h −1 70 kg −1 , volume of distribution (Vfree) 1700 (CV 44.9%) litre 70 kg −1 , absorption half-life (Tabsfree) 0.175 (CV 83.7%) h 70 kg −1 . There was no effect attributable to PNA on CL or V. Time to peak plasma concentration (Tmax) was 0.82 (CV 18%) h. Peak plasma concentration (Cmax) was 0.69 (CV 25%) µg ml −1 for total levobupivacaine and 0.09 (CV 37%) µg ml −1 for unbound levobupivacaine. Conclusions Clearance in infants is approximately half that described in adults, suggesting immaturity of P450 CYP3A4 and CYP1A2 enzyme isoforms that metabolize levobupivacaine in infants. This lower clearance delays Tmax, which was noted to occur approximately 50 min after administration of caudal epidural levobupivacaine.

Objective: We aimed to determine the pharmacokinetics (PK) of N-acetylcysteine (NAC) at rest and during exercise when given by continuous intravenous infusion intended to maintain relatively constant plasma concentrations. Methods: Plasma concentrations of NAC were measured in 24 healthy male subjects during and after a two-stage intravenous infusion designed to provide constant NAC concentrations during cycling exercise, including intense exercise to fatigue. Results: A three-compartment, open PK model was the best fit using population PK analysis with NONMEM. Whole-body clearance (CL) was 0.58 l kg−1 h−1 (95% CI 0.44–0.72) for reduced NAC (NACR) and 0.16 (0.13–0.20) l kg−1 h−1 for total NAC (NACT). The central volume of distribution (V1) was 0.064 (0.008–0.12) l kg−1 for NACR and 0.037 (0.02–0.06) l kg−1 for NACT. Exercise was a significant covariate in the model, resulting in a 25 and 23% reduction in CL of NACR and NACT, respectively. V1 in our subjects was smaller than expected, resulting in higher-than-anticipated initial concentrations of NAC. Despite these findings, the incidence of adverse effects attributable to NAC was minimal without using prophylactic or concomitant drug therapy. Conclusions: NAC can be given to healthy exercising men by intravenous infusion and to the plasma concentrations seen in this study with minimal adverse effects due to the drug. The PK parameters of NAC at rest in volunteers are consistent with previously reported values and are significantly altered by vigorous cycling exercise.

Areas of insensibility produced by neuraxial anesthesia or peripheral nerve blocks can be detected during general anesthesia by failure of noxious stimulation to trigger pupillary reflex dilation. We examined the latency of pupillary reflex dilation and the effect of fentanyl on the latency of reflex dilation during anesthesia in nine volunteers. We hypothesized that the reflex was generated by slowly conducting C nociceptive fibers and would be significantly delayed if a distal dermatome (L4) was stimulated compared with a proximal dermatome (C5). We also hypothesized that fentanyl would prolong the latency and alter the shape of the reflex. After induction of general anesthesia, pupillary reflex dilation was measured with an infrared pupillometer every 5 min after stimulations of the L4 and C5 dermatomes. Fentanyl (3 μg/kg) was then given intravenously. Pupillary reflex dilation latencies were calculated by examining each individual measurement. After 3 h, naloxone (400 μg) was given intravenously; anesthesia was then discontinued. Pupillary reflex dilation had a long latency and consisted of distinct early and late phases. No differences were found between latencies of reflex dilation after simulation of L4 and C5 dermatomes either before or after fentanyl administration. Fentanyl at high concentrations essentially eliminated pupillary reflex dilation; but over the 180-min observation period, first early and then late dilation returned. Fentanyl produced a small increase in the latency of the initial early dilation. We conclude that pupillary reflex dilation during anesthesia is not initiated by slowly conducting C fibers and that fentanyl depresses the reflex in a stereotypical manner.

Recent studies have indicated that despite stringent sterilization processes, the reusable silicone laryngeal mask airway (LMA) has the potential for disease transmission through residual biological debris. As a result, a polyvinyl chloride (PVC) disposable LMA has been introduced. This randomized trial involved 138 spontaneously ventilating adult patients who underwent elective surgery requiring airway management with an LMA to determine whether there is a clinical difference between the disposable Portex® LMA (PLMA) and the standard reusable LMA in terms of ease of insertion, intra-operative cuff pressures and postoperative incidence of sore throat. There was no significant difference in first attempt insertion success rates (79% vs 84%) or difference in the incidence of postoperative sore throat observed between the two groups. Cuff pressure increases with nitrous oxide anaesthesia were significantly larger with the reusable LMA. The disposable PLMA provided a suitable airway in spontaneously ventilating patients without the risk of disease transmission inherent in a reusable device.

BACKGROUND: Sedation practice, especially when non-anaesthesia personnel are involved, requires efficient anaesthetic depth monitoring. Therefore, we used prediction probability (PK) to evaluate the performance of the bispectral index (BIS) of the EEG and automated responsiveness test (ART) to predict sedation depth and loss of subject's responsiveness during propofol sedation, with and without N2O. METHODS: Twenty volunteers were studied during propofol administration with (N2O) and without (Air) N2O. The protocol consisted of sequential 15-min cycles. After a control period, propofol was infused to a target effect-site concentration of 0.25 microg/ml (N2O) or 1.5 microg/ml (Air), which was subsequently increased by 0.25 or 0.5 microg/ml, respectively, until loss of responsiveness was detected by loss of response to command [observer's assessment of alertness/sedation (OAA/S) score

BACKGROUND We evaluated a new, integrated, covariate-adjusted, target-controlled infusion system during sedation with propofol combined with 50% nitrous oxide (N2O) and with propofol only (Air). METHODS The protocol consisted of sequential 15-minute cycles in 20 volunteers. After a 15-minute control period, propofol was infused to an initial target effect-site concentration of 0.25 microg x ml-1 (N2O) or 1.5 microg x ml-1 (Air). Subsequently, the target effect-site concentration was increased by 0.25 (N2O) or 0.5 microg x ml-1 (Air) for 15 min This sequence was continued until the volunteers lost consciousness as defined by an Observer's Assessment Alertness/Sedation (OAA/S) score = 2. RESULTS Venous plasma propofol concentrations at the beginning(9 elapsed minutes) and end(15 elapsed minutes) of the pseudo-steady state period differed by only 0.00 +/- 0.16 microg x ml-1 (P = 0.78) during the N2O and 0.00 +/- 0.25 microg x ml-1 (P = 0.91) during the Air trial. OAA/S scores and bispectral index values, as surrogate measures of pharmacodynamic effect, were not different during this time in either trial. The median(25th, 75th percentiles) of the median performance error (%) was -13 (-24, -1) during the N2O and -18 (-26, -9) during the Air trial. The median absolute performance error (%) was 17 (10, 24) in the N2O and 22 (12, 28) in Air trial. The divergence (%/h) was -10 (-26, 4) in the N2O and 14 (-21, 26) in Air trial. The wobble was 7 (5, 10) in the N2O and 6 (4, 8) in the Air trial. CONCLUSIONS When tested with venous blood samples, our TCI system for propofol, using a covariate-adjusted, integrated pharmacokinetic model to target effect-site concentrations, demonstrated a clinically acceptable accuracy and stability during mild to moderate sedation.

Background and Purpose— Hypothermia might prove to be therapeutically beneficial in stroke victims; however, even mild hypothermia provokes vigorous shivering. Meperidine and dexmedetomidine each linearly reduce the shivering threshold (triggering core temperature) with minimal sedation. We tested the hypothesis that meperidine and dexmedetomidine synergistically reduce the shivering threshold without producing substantial sedation or respiratory depression. Methods— We studied 10 healthy male volunteers (18 to 40 years) on 4 days: (1) control (no drug); (2) meperidine (target plasma level 0.3 μg/mL); (3) dexmedetomidine (target plasma level 0.4 ng/mL); and (4) meperidine plus dexmedetomidine (target plasma levels of 0.3 μg/mL and 0.4 ng/mL, respectively). Lactated Ringer’s solution (≈4°C) was infused through a central venous catheter to decrease tympanic membrane temperature by ≈2.5°C/h; mean skin temperature was maintained at 31°C. An increase in oxygen consumption >25% of baseline identified the shivering threshold. Sedation was evaluated by using the Observer’s Assessment of Sedation/Alertness scale. Two-way repeated-measures ANOVA was used to identify interactions between drugs. Data are presented as mean±SD; P Results— The shivering thresholds on the study days were as follows: control, 36.7±0.3°C; dexmedetomidine, 36.0±0.5°C ( P P P P =0.19). There was trivial sedation with either drug alone or in combination. Respiratory rate and end-tidal P co 2 were well preserved on all days. Conclusions— Dexmedetomidine and meperidine additively reduce the shivering threshold; in the small doses tested, the combination produced only mild sedation and no respiratory toxicity.

A validated method for the determination of remifentanil in human blood, applicable to all therapeutic concentrations, using capillary GC with nitrogen-specific detection and fentanyl as the internal standard has been developed. Citrated whole blood samples were extracted into 1-chlorobutane following precipitation of proteins with methanol. The drugs were back extracted into 10 mM HCl and re-extracted into methanol-1-chlorobutane. The extracts were reconstituted in methanol and injected onto a 25-m BPX-5 column. The lower limit of quantitation was 0.2 ng/ml with within- and between-day coefficients of variation of less than 15%.

Background The authors evaluated a device designed to provide conscious sedation with propofol (propofol-air), or propofol combined with 50% nitrous oxide (N2O; propofol-N2O). An element of this device is the automated responsiveness test (ART), a method for confirming that patients remain conscious. The authors tested the hypotheses that the ART predicts loss of consciousness and that failure to respond to the ART precedes sedation-induced respiratory or hemodynamic toxicity. Methods The protocol consisted of sequential 15-min cycles in 20 volunteers. After a 15-min control period, propofol was infused to an initial target effect-site concentration of 0.0 microg/ml with N2O or 1.5 microg/ml with air. Subsequently, the propofol target effect-site concentration was increased by a designated increment (0.25 and 0.5 microg/ml) and the process repeated. This sequence was continued until loss of consciousness, as defined by an Observer's Assessment of Alertness/Sedation (OAA/S) score of 10/20 or less, or until an adverse physiologic event was detected. Results The OAA/S score at which only 50% of the volunteers were able to respond to the ART (P50) during propofol-N2O was 11.1 of 20 (95% confidence interval [CI]: 10.6-11.8); the analogous P50 was 11.8 of 20 (95% CI: 11.4-12.3) with propofol-air. Failure to respond to the ART occurred at a plasma propofol concentration of 0.7 +/- 0.6 microg/ml with propofol-N2O and 1.6 +/- 0.6 microg/ml with propofol-air, whereas loss of consciousness occurred at 1.2 +/- 0.8 microg/ml and 1.9 +/- 0.7 microg/ml, respectively. There were no false-normal ART responses. Conclusion The ART can guide individual titration of propofol because failure to respond to responsiveness testing precedes loss of consciousness and is not susceptible to false-normal responses. The use of N2O with propofol for conscious sedation decreases the predictive accuracy of the ART.

Background Epidural analgesia is frequently associated with hyperthermia during labor and in the postoperative period. The conventional assumption is that hyperthermia is caused by the technique, although no convincing mechanism has been proposed. However, pain in the "control" patients is inevitably treated with opioids, which themselves attenuate fever. Fever associated with infection or tissue injury may then be suppressed by opioids in the "control" patients while being expressed normally in patients given epidural analgesia. The authors therefore tested the hypothesis that fever in humans is manifested normally during epidural analgesia, but is suppressed by low-dose intravenous opioid. Methods The authors studied eight volunteers, each on four study days. Fever was induced each day by 150 IU/g intravenous interleukin 2. Volunteers were randomly assigned to: (1) a control day when no opioid or epidural analgesia was given; (2) epidural analgesia using ropivacaine alone; (3) epidural analgesia using ropivacaine in combination with 2 microg/ml fentanyl; or (4) intravenous fentanyl at a target plasma concentration of 2.5 ng/ml. Results Fentanyl halved the febrile response to pyrogen, decreasing integrated core temperature from 7.0 +/- 3.2 degrees C. h on the control day, to 3.8 +/- 3.0 degrees C. h on the intravenous fentanyl day. In contrast, epidural ropivacaine and epidural ropivacaine-fentanyl did not inhibit fever. The fraction of core-temperature measurements that exceeded 38 degrees C was halved by intravenous fentanyl, and the fraction exceeding 38.5 degrees C was reduced more than fivefold. Conclusions These data support the authors' proposed mechanism for hyperthermia during epidural analgesia. Fever during epidural analgesia should thus not be considered a complication of the anesthetic technique per se.

OBJECTIVE Manifestation of intraoperative fever is impaired by volatile anesthetics and muscle relaxants. Opioids are common anesthetic adjuvants and remain the dominant treatment for postoperative surgical pain and sedation of critically ill patients. The effect of opioids on normal thermoregulatory control is well established. However, the extent to which these drugs might inhibit fever remains unknown. Accordingly, we tested the hypothesis that relatively low plasma concentrations of the mu-receptor agonist alfentanil reduce fever magnitude. DESIGN Prospective, randomized, crossover study. SETTING Outcomes Research Laboratory, at the Department of Anesthesia and Perioperative Care, University of California, San Francisco. PATIENTS Eight healthy male volunteers, aged 25-31 yrs, each studied on three separate days. INTERVENTION Each volunteer was given an intravenous injection of 30 IU/g interleukin (IL)-2, followed 2 hrs later by 70 IU/g. One hour after the second dose, the volunteers were randomly assigned to three doses of alfentanil: a) none (control); b) a target plasma concentration of 100 ng/mL; and c) a target concentration of 200 ng/mL. Opioid administration continued for 5 hrs. METHODS AND MAIN RESULTS Alfentanil significantly reduced the febrile response to pyrogen, decreasing integrated tympanic membrane temperatures from 7.5+/-2.2 degrees C x hr on the control day, to 4.9+/-1.5 degrees C x hr with 100 ng/mL alfentanil, and to 5.1+/-1.7 degrees C x hr with 200 ng/mL alfentanil (p = .011). Peak temperatures were also significantly reduced from 38.5+/-0.4 degrees C on the control day, to 38.0+/-0.4 degrees C on the 100 ng/mL-alfentanil day and 38.0+/-0.6 degrees C on the 200-ng/mL day (p = .019). Plasma cytokine concentrations increased after IL-2 administration, roughly in proportion to the elevation in core temperature. However, cytokine concentrations did not differ significantly among the treatment groups. CONCLUSION Alfentanil significantly reduced the febrile response to IL-2 administration. However, the reduction was comparable at plasma concentrations near 100 and 200 ng/mL. These data indicate that concentrations of opioids commonly observed in critical care patients significantly inhibit the manifestation of fever.

Initial treatments for fever include the amelioration of underlying causes and administration of antipyretic medications. However, patients who fail these treatments are often actively cooled, which may be counterproductive because decreasing skin temperature increases the thermoregulatory core target temperature. Cooling may also provoke metabolic and autonomic stress and thermal discomfort.We studied 9 subjects, each on 3 days. Fever was induced each day with 100,000 IU/kg of interleukin-2 administered intravenously (elapsed time zero). Randomly assigned treatments were 1) control (a cotton blanket), 2) cooling (forced air at 15 degrees C), or 3) self-adjust (forced-air warming adjusted to comfort). Treatments were maintained for 3 to 8 elapsed hours.Peak core temperatures (mean +/- SD) were 38.4 +/- 0.5 degrees C on the control day, 38.1 +/- 0.5 degrees C on the cooling day, and 38.5 +/- 0.4 degrees C on the self-adjust day. Integrated core temperatures were 6.0 +/- 1.6 degrees C x h on the control day, 5.7 +/- 2.2 degrees C x h on the cooling day, and 6.4 +/- 1.2 degrees C x h on the self-adjust day. Neither peak nor integrated core temperatures differed significantly on the 3 days. Shivering was common on the cooling day but otherwise rare. Oxygen consumption was normal on the control and self-adjust days but increased 35% to 40% during cooling (P = 0.0001). Mean arterial pressure and plasma norepinephrine and epinephrine concentrations were significantly greater during cooling (P0.05). On a self-reported thermal comfort scale, the subjects were miserable during cooling and significantly more comfortable on the self-adjust than control day (P0.05).We conclude that active cooling should be avoided in unsedated patients with moderate fever, because it does not reduce core temperature but does increase metabolic rate, activate the autonomic nervous system, and provoke thermal discomfort.

Inhalation induction with sevoflurane was compared with propofol or sevoflurane/propofol in 60 unpremedicated adults. Target concentrations for the three groups (with 60% nitrous oxide) were 3% end-tidal sevoflurane, 12 mg/l propofol and 1.5% sevoflurane/6 mg/l propofol respectively, prior to insertion of a laryngeal mask airway (LMA) at 10 minutes. Induction of anaesthesia was satisfactory in each group, but movement response to LMA insertion was observed in 20 patients (least in the sevoflurane group). Cardiovascular responses were similar except for a lower heart rate in the sevoflurane group. EEG bispectral index suggested a greater depth of anaesthesia in the inhalation induction group. A bispectral index of 60 separated patients responding to LMA insertion from nonresponders (P=0.006), and had a sensitivity of 68% and specificity 70%. Movement response was not predicted by cardiovascular changes.

The analgesic tramadol inhibits the neuronal reuptake of norepinephrine and 5-hydroxytryptamine, facilitates 5-hydroxytryptamine release, and activates mu-opioid receptors. Each of these actions is likely to influence thermoregulatory control. We therefore tested the hypothesis that tramadol inhibits thermoregulatory control. Eight volunteers were evaluated on four study days, on which they received no drugs, tramadol 125 mg, tramadol 250 mg, and tramadol 250 mg with naloxone, respectively. Skin and core temperatures were gradually increased until sweating was observed and then decreased until vasoconstriction and shivering were detected. The core temperature triggering each response defined its threshold. Tramadol decreased the sweating threshold by -1.03 +/- 0.67 degrees C microgram-1.mL (r2 = 0.90 +/- 0.12). Tramadol also decreased the vasoconstriction threshold by -3.0 +/- 4.0 degrees C microgram-1.mL (r2 = 0.94 +/- 0.98) and the shivering threshold by -4.2 +/- 4.0 degrees C microgram-1.mL(r2 = 0.98 +/- 0.98). The sweating to vasoconstriction interthreshold range nearly doubled from 0.3 +/- 0.4 degree C to 0.7 +/- 0.6 degree C during the administration of large-dose tramadol (P = 0.04). The addition of naloxone only partially reversed the thermoregulatory effects of tramadol. The thermoregulatory effects of tramadol thus most resemble those of midazolam, another drug that slightly decreases the thresholds triggering all three major autonomic thermoregulatory defenses. In this respect, both drugs reduce the "setpoint" rather than produce a generalized impairment of thermoregulatory control. Nonetheless, tramadol nearly doubled the interthreshold range at a concentration near 200 ng/mL. This indicates that tramadol slightly decreases the precision of thermoregulatory control in addition to reducing the setpoint.The authors evaluated the effects of the analgesic tramadol on the three major thermoregulatory responses: sweating, vasoconstriction, and shivering. Tramadol had only slight thermoregulatory effects. Its use is thus unlikely to provoke hypothermia or to facilitate fever.

This article describes two prospective, randomized, double-blind clinical trials designed to investigate this. Trial 1 compared a conventional local anaesthetic agent (100 mg bupivacaine) injected intra-articularly (i.a.) with a control (normal saline) and 1 mg of i.a. morphine. No significant difference was noted in the first 4 hours between the groups with respect to visual analogue pain (VAS) scores. However, at 6 and 24 hours, the group of patients who received 1 mg i.a. morphine recorded lower pain scores and required less supplementary analgesia. Trial 2 assessed the dose response relationship for i.a. morphine comparing 5 mg intravenous (i.v.) morphine (control) with 1 mg and 5 mg i.a. morphine. At early time points (1, 2, and 4 hours) similar VAS pain scores were recorded for both 5 mg i.v. morphine and 5 mg i.a. morphine, both significantly lower than the group receiving 1 mg i.a. morphine. At 6 and 24 hours, 5 mg of i.a. morphine produced significantly lower pain scores, less analgesic requirement, and less sleep disturbance on the first postoperative night than the other groups. It can be concluded from these two studies that 5 mg i.a. was the most effective analgesic following knee arthroscopy.

Background Estimation of the mu-agonist opioid effect in anesthetized and paralyzed patients is often imprecise and can be obscured by concomitant administration of drugs that affect the sympathetic nervous system, such as beta-adrenergic blocking agents. As an alternative to hemodynamic measures of opioid effect, the authors tested the hypothesis that the pupillary light reflex or pupillary reflex dilation correlated with alfentanil concentrations during isoflurane anesthesia. Methods Six volunteers were anesthetized on 4 days with 0.8% isoflurane. Alfentanil was administered intravenously to target total plasma concentrations of 0, 25, 50, and 100 ng/ml. A 5-s tetanic electrical stimulus was applied to the skin. Pupil size and the pupillary light reflex were recorded before and after alfentanil administration, and before and for 8 min after the stimulus. Results Alfentanil exponentially impaired reflex pupillary dilation, decreasing the maximum response amplitude from 5 mm at 0 ng/ml, to 2.3 mm at 25 ng/ml, to 1.0 mm at 50 ng/ml, and finally to 0.2 mm at 100 ng/ml. In contrast, only the highest concentration of alfentanil depressed the dilation of the pupil in the first 2 s after the stimulus. Alfentanil administration had no effect on the pupillary light reflex. Conclusions Dilation of the pupil in response to a noxious stimulus is a measure of opioid effect in isoflurane-anesthetized volunteers. In contrast, the pupillary light reflex is unaffected by alfentanil during isoflurane anesthesia. These data suggest that stimulus-induced pupillary dilation may be used to evaluate the analgesic component of a combined volatile and opioid anesthetic.

Background and Objectives Pupillary dilation in response to dermatomal electrical stimulation is one method of determining sensory block level during combined epidural and general anesthesia. Use of this technique may, however, be confounded by systemic absorption of epidurally administered local anesthetics. Accordingly, the effects of intravenous lidocaine on the magnitude and duration of reflex pupillary dilation were evaluated. Methods Six volunteers were each anesthetized twice with desflurane 3.5-6.0%. During one anesthetic, intravenous lidocaine was administered to a plasma concentration of 5.3 ± 1.5 μg/mL. When the plasma concentrations were stable, a 5-second tetanic electrical stimulus was applied. Pupil size was then recorded for 8 minutes. Results Lidocaine, at plasma concentrations near 5 μg/mL, did not significantly alter the pupillary response to electrical stimulation. In contrast, stimulus-induced increase in heart rate was obliterated. Painful stimulation did not increase systolic blood pressure in either case. Conclusions Typical plasma lidocaine concentrations observed during epidural anesthesia are unlikely to prevent the use of pupillary responses to evaluate sensory block level.

To target appropriate drug concentrations and to facilitate comparisons between drugs, the potency of propofol must be firmly established. We therefore determined the arterial blood propofol concentration preventing movement in 50% of patients after skin incision and the ability of arterial blood pressure and heart rate to predict movement after incision. Fifteen healthy women scheduled for breast surgery were randomly assigned to computer-targeted propofol blood concentrations. No other drugs were administered. Fifteen minutes after starting the propofol infusion, a 5-cm skin incision was made. Patients were observed for gross purposeful movement for 1 min. Arterial blood was sampled for propofol to confirm steady-state blood concentrations. Arterial blood pressure and heart rate were measured noninvasively. Logistic regression was used to calculate the propofol blood concentrations and arterial blood pressures at which 50% and 95% of patients did not move after skin incision (CP50 and CP95, MABP50 and MABP95, respectively). The CP50 and CP95 values for propofol were 14.3 +/- 1.6 microg/mL (mean +/- SE) and 20.6 microg/mL, respectively. The MABP50 and MABP95 values were 63 +/- 4 mm Hg and 43 mm Hg, respectively. Heart rate did not differ significantly in patients who moved and who did not move. Propofol blood concentrations required to prevent movement in most patients resulted in significant arterial hypotension.

OBJECTIVE: To examine the effects of cardiopulmonary bypass (CPB) on total and unbound plasma concentrations of propofol and midazolam when administered by continuous infusion during cardiac surgery. DESIGN: Prospective clinical study. SETTING: University hospital. PARTICIPANTS: Twenty-four adult patients undergoing cardiac surgery. INTERVENTIONS: Patients received either propofol or midazolam to supplement fentanyl anesthesia. Twelve patients received a propofol bolus (1 mg/kg) followed by an infusion of 3 mg/kg/hr. A second group received midazolam, 0.2 mg/kg bolus, followed by an infusion of 0.07 mg/kg/hr. MEASUREMENTS AND MAIN RESULTS: Blood sample were collected from the radial artery cannula at 0, 2, 4, 8, 8, 10, 15, 20 minutes and then every 10 minutes before CPB, at 1, 2, 3, 4, 6, 10, 15, 20 minutes and then each 10 minutes during CPB. On weaning from CPB samples were collected at 0, 5, 10 and 20 minutes. Plasma binding, total and unbound propofol and midazolam concentrations were determined by ultrafiltration and high-pressure liquid chromatography (HPLC). CPB resulted in a fall in total propofol and midazolam plasma concentrations, but the unbound concentrations remained stable. The propofol unbound fraction increased from 0.22 +/- 0.06% to 0.41 +/- 0.17%. The midazolam unbound fraction increased from 5.6 +/- 1.0% to 11.2 +/- 2.1%. CONCLUSIONS: Unbound concentrations of propofol and midazolam are not affected by cardiopulmonary bypass. Total intravenous anesthesia algorithms do not need to be changed to achieve stable unbound plasma concentrations when initiating CPB.

A high-performance liquid chromatographic method for the determination of eltanolone in plasma has been developed. Plasma samples containing eltanolone were diluted with acetonitrile to precipitate plasma proteins, and derivatized with 2,4-dinitrophenylhydrazine before direct injection onto a C18 column. The mobile phase was acetonitrile-water (70:30, v/v) containing 0.1% trifluoroacetic acid and detection was by UV absorbance at 367 nm. The quantitation limit was 0.020 microg/ml. The method has proven to be rapid, precise and sensitive in the range of concentrations found during and following intravenous anaesthesia.

Background Meperidine administration is a more effective treatment for shivering than equianalgesic doses of other opioids. However, it remains unknown whether meperidine also profoundly impairs other thermoregulatory responses, such as sweating or vasoconstriction. Proportional inhibition of vasoconstriction and shivering suggests that the drug acts much like alfentanil and anesthetics but possesses greater thermoregulatory than analgesic potency. In contrast, disproportionate inhibition would imply a special antishivering mechanism. Accordingly, the authors tested the hypothesis that meperidine administration produces a far greater concentration-dependent reduction in the shivering than vasoconstriction threshold. Methods Nine volunteers were each studied on three days: 1) control (no opioid); 2) a target total plasma meperidine concentration of 0.6 microgram/ml (40 mg/h); and 3) a target concentration of 1.8 micrograms/ml (120 mg/h). Each day, skin and core temperatures were increased to provoke sweating and then subsequently reduced to elicit vasoconstriction and shivering. Core-temperature thresholds (at a designated skin temperature of 34 degrees C) were computed using established linear cutaneous contributions to control sweating (10%) and vasoconstriction and shivering (20%). The dose-dependent effects of unbound meperidine on thermoregulatory response thresholds was then determined using linear regression. Results are presented as means +/- SDs. Results The unbound meperidine fraction was approximately 35%. Meperidine administration slightly increased the sweating threshold (0.5 +/- 0.8 degree C.microgram-1.ml; r2 = 0.51 +/- 0.37) and markedly decreased the vasoconstriction threshold (-3.3 +/- 1.5 degrees C.microgram-1.ml; r2 = 0.92 +/- 0.08). However, meperidine reduced the shivering threshold nearly twice as much as the vasoconstriction threshold (-6.1 +/- 3.0 degrees C.microgram-1.ml; r2 = 0.97 +/- 0.05; P = 0.001). Conclusions The special antishivering efficacy of meperidine results at least in part from an uncharacteristically large reduction in the shivering threshold rather than from exaggerated generalized thermoregulatory inhibition. This pattern of thermoregulatory impairment differs from that produced by alfentanil, clonidine, propofol, and the volatile anesthetics, all which reduce the vasoconstriction and shivering thresholds comparably.

Non-steroidal anti-inflammatory drugs (NSAIDs) provide effective analgesia after orthopaedic surgery and reduce opioid requirements. The need for parenteral NSAIDs with peripheral surgery is controversial. In this study 10 patients were treated with oral tenoxicam 20 mg preoperatively, and at 4 hours and 28 hours after knee ligament reconstruction surgery. Plasma concentrations of tenoxicam, an NSAID with a long elimination half-life, were measured for 10 days. All patients received patient-controlled intravenous morphine postoperatively, which delayed absorption of the second and third tenoxicam doses. However, plasma concentrations of tenoxicam were achieved and maintained for the five-day surgical admission above the level considered to produce effective analgesia. Oral analgesic administration is a simple and feasible option in the perioperative period.

In summary, both mu-receptor and combined mu/kappa-receptor opioids impair thermoregulatory control. Alfentanil, a pure mu-receptor agonist slightly increased the thresholds for sweating and markedly decreased the thresholds for vasoconstriction and shivering. However, the vasoconstriction-to-shivering range remained normal during alfentanil administration as it does during general anesthesia. Meperidine, a combined mu- and kappa-receptor agonist, also slightly increased the threshold for sweating and reduced the thresholds for vasoconstriction. However, meperidine reduced the shivering threshold twice as much as the vasoconstriction threshold, thus significantly increasing the vasoconstriction-to-shivering range. Furthermore, shivering during meperidine administration, once triggered, was of low intensity suggesting that the drug also decreased the gain of shivering. The special antishivering action of meperidine appears to result, at least in part, from its kappa-receptor activity.

Background The transversus abdominis plane (TAP) block is a regional anaesthetic technique that blocks abdominal wall somatic afferent nerves. We conducted a prospective observational study to evaluate the venous plasma concentrations of ropivacaine during a continuous TAP infusion. Methods Twenty patients who were planned to undergo intra-abdominal cavity surgery requiring a mid-line laparotomy incision were enrolled. Patients were excluded if they had a history of chronic pain, opioid tolerance, renal or hepatic impairment, or contraindication to study medications. Subjects received a standardized general anaesthetic, and at the completion of surgery, ultrasound-guided subcostal or posterior TAP blocks and catheters. A TAP infusion of 2 mg ml −1 ropivacaine was administered for 72 h after operation. Data collection during the 72 h included morphine requirements, pain scores, and plasma ropivacaine levels. Results TAP blocks and catheters were successfully inserted in all recruited subjects. The fourth subject experienced neurological symptoms attributed to local anaesthetic toxicity, but did not have high plasma ropivacaine concentrations. However, the protocol was amended for the subsequent 16 subjects, to a weight-based dosing regimen. The range of total plasma ropivacaine concentrations was 0.98–3.41 mg litre −1 for posterior infusions and 0.96–3.48 mg litre −1 for subcostal infusions. Four subjects had total ropivacaine levels >3.4 mg litre −1 . The range of unbound plasma ropivacaine concentrations was 0.022–0.135 mg litre −1 for posterior infusions and 0.031–0.120 mg litre −1 for subcostal infusions. Conclusion Given the potential for high plasma concentrations from a bilateral TAP infusion technique, attention should be paid to individualized dosing strategies.

Background The transversus abdominis plane (TAP) block involves injecting a large volume of local anaesthetic between the muscles of the abdominal wall. Plasma concentrations of ropivacaine after gynaecological laparotomy are potentially high enough to result in systemic toxicity, and there are pharmacokinetic reasons why pregnancy may increase susceptibility to local anaesthetic toxicity. Methods Adult female patients (n=30) undergoing elective Caesarean section under spinal anaesthesia received bilateral ultrasound-guided TAP blocks after wound closure (2.5 mg kg−1 of ropivacaine diluted to 40 ml). Venous blood samples were collected at 10, 20, 30, 45, 60, 90, 120, 180 and 240 min following the block. Blood samples were assayed for total and free ropivacaine concentrations. Patients were assessed for symptoms of local anaesthetic toxicity. Results The mean [standard deviation ( sd )] peak total concentration of ropivacaine occurred at 30 min post-injection and was 1.82 (0.69) μg ml−1. The maximum detected concentration in any patient was 3.76 μg ml−1 (at 10 min post-injection). Three patients reported symptoms of mild neurotoxicity, and the mean ( sd ) peak levels were elevated in these patients, 2.70 (0.46) µg ml−1. Conclusions TAP blocks can result in elevated plasma ropivacaine concentrations in patients undergoing Caesarean section, which may be associated with neurotoxicity.

Perioperative hypothermia usually results largely from pharmacologic inhibition of normal thermoregulatory control.Midazolam is a commonly used sedative and anesthetic adjuvant whose thermoregulatory effects are unknown. We therefore tested the hypothesis that midazolam administration impairs thermoregulatory control. Eight volunteers were studied on 2 days each, once without drug and once at a target total plasma midazolam concentration of 0.3 micro gram/mL (corresponding to administration of approximate equals 40 mg over approximate equals 4 h). Each day, skin and core temperatures were increased sufficiently to provoke sweating, and then reduced to elicit peripheral vasoconstriction and shivering. We mathematically compensated for changes in skin temperature using the established linear cutaneous contributions to control of each response. From these calculated thresholds (core temperatures triggering responses at a designated skin temperature of 34 degrees C), we determined the thermoregulatory effects of midazolam. The sweating threshold was decreased approximate equals 0.3 degrees C by midazolam administration: 37.3 +/- 0.2 degrees C vs 37.0 +/- 0.3 degrees C (P = 0.0004, paired t-test). Midazolam decreased the core temperature that triggered vasoconstriction somewhat more: 37.1 +/- 0.2 degrees C vs 36.3 +/- 0.5 degrees C (P = 0.0002). Similarly, midazolam decreased the shivering threshold: 35.9 +/- 0.3 degrees C vs 35.3 +/- 0.6 degrees C (P = 0.03). The sweating-to-vasoconstriction (interthreshold) range, therefore, increased from 0.2 +/- 0.1 degrees C to 0.7 +/- 0.3 degrees C (P = 0.002). Although statistically significant, this relatively small increase contrasts markedly with the 3-5 degrees C interthreshold ranges produced by clinical doses of volatile anesthetics, propofol, and opioids. Thus, plasma concentrations of midazolam far exceeding those used routinely produce relatively little impairment of thermoregulatory control. (Anesth Analg 1995;81:393-8)

Background The inability of edrophonium to rapidly reverse a deep nondepolarizing neuromuscular block may be due to inadequate dosage or a ceiling effect to antagonism of neuromuscular block by edrophonium. A ceiling effect means that only a certain level of neuromuscular block could be antagonized by edrophonium. Neuromuscular block greater than this could not be completely antagonized irrespective of the dose of edrophonium administered. The purpose of this study was to determine whether a ceiling effect occurred for antagonism of an atracurium-induced neuromuscular block by edrophonium and, if so, the maximum level of block that could be antagonized by edrophonium. Methods In 30 adult patients, atracurium was administered to maintain a constant neuromuscular block. The level of block varied between patients. Evoked adductor pollicis twitch tension was monitored. Incremental doses of edrophonium were administered while the infusion of atracurium continued. Increments were given until adequate recovery occurred, as defined by a train-of-four (TOF) ratio > or = 70%, or until no further antagonism of the block could be achieved. The probability of being able to effect adequate recovery by antagonism with edrophonium was determined using a logistic regression model. Cumulative dose-response curves were constructed using the logit transformation of the neuromuscular effect versus the logarithm of the cumulative dose of edrophonium. Results In 14 patients with a block of 25-77% depression of the first twitch response, antagonism by edrophonium to a TOF ratio > or = 70% was possible, whereas in 16 patients with a 60-92% depression of T1, a TOF ratio > or = 70% was not achievable, indicating that a ceiling effect for antagonism by edrophonium occurred. A block of 67 +/- 3% (mean +/- SE) had a 50% probability of adequate antagonism. In patients in whom block was antagonized to a TOF ratio < 70%, 95% of the peak antagonistic effect occurred with an edrophonium dose of 0.8 +/- 0.33 mg.kg-1 (mean +/- SD). Conclusions There is a maximum level of neuromuscular block that can be antagonized by edrophonium to effect adequate recovery. The level corresponds approximately to the reappearance of the fourth response to TOF stimulation. It is probably safest to wait until this level of block occurs before edrophonium is given for reversal. Earlier administration will not hasten recovery.

Objective: To investigate the relationship of glutamate and glutamate transporter expression in human gliomas and surrounding peritumoral brain to the presence of tumor-associated seizures (TAS). Methods: We studied a retrospective (group 1: 190 patients) and then a prospective (group 2: 98 patients) cohort of patients who underwent a craniotomy for a supratentorial glioma. Tumor and peritumor tissue specimens were assayed for glutamate concentration and expression of glial glutamate transporters. Differences between the seizure (TAS) and seizure-free (non-TAS) groups were compared. Results: A total of 42% of patients had TAS, with 95% of seizures first occurring preoperatively. Clinical factors independently associated with risk of TAS were younger age, temporal lobe location, and tumors with oligodendroglial components. Molecular features in tumor specimens associated with TAS were higher glutamate concentrations, reduced EAAT2 expression, and increased system X c − expression. In group 2, these results were also replicated in the peritumor tissue. Logistic regression analysis identified raised glutamate concentrations in tumor and peritumor tissue, increased expression of peritumor system X c − , younger age, temporal lobe location, and tumors with oligodendroglial components as independently predictive of preoperative seizures. Conclusion: Relative increased glutamate concentration in gliomas, and altered glutamate transporter expression, are associated with the presence of TAS and may play a mechanistic role in their pathogenesis.

Interpleural infusions (24 hr) were given to 14 adults (29-81 yr) having surgery via right subcostal incisions. Patient-controlled analgesia with morphine was also available for 72 hours following surgery. An infusion of 0.25% bupivacaine with adrenaline 1/400,000 was commenced at 0.1 ml/kg/hr at the conclusion of surgery after an initial 20 ml bolus. The 24 hr cumulative morphine dose increased by 62% (P < 0.01) on the second postoperative day after the bupivacaine infusion was ceased, but the pain score did not change. There was no clinical evidence of bupivacaine toxicity although the maximum bupivacaine concentration ranged from 0.74-6.52 mg/l, mean 2.90 (SEM 0.44) mg/l and vascular uptake was rapid in two patients. The concentration of S-bupivacaine was consistently greater than R-bupivacaine (P < 0.05) and total body clearance was less. The unbound bupivacaine fraction also changed from 3.6% (SEM 0.6) at the start of the infusion to 2.0% (SEM 0.3) at 24 hr (P < 0.005). The total body clearance of each enantiomer was reduced during the 24 hours (P < 0.001). No relationship between pharmacokinetic parameters and weight, age or sex was found (P>0.25 for each). Variation between patients was reduced when parameters were estimated for the free (unbound) bupivacaine (P < 0.001).

The optimal method of oxygen supplementation during upper gastrointestinal endoscopy has not been clearly defined. The aim of this study was to compare oxygen supplementation via nasal prongs with that via a catheter passed into the low oropharynx to eliminate the effect of mouth breathing. Patients were stratified according to the American Society of Anesthesiologists (ASA) classification of physical status into lower-risk (ASA 1 and 2) and higher-risk (ASA 3) groups. The lower-risk group received intranasal, intrapharyngeal, or no oxygen supplementation, and higher-risk patients received either intranasal or intrapharyngeal oxygen. Continuous arterial oxygen saturation (SpO2) was recorded, using a pulse oximeter, before and during endoscopy. Critical desaturations (SpO2 < or = 90%), minimum SpO2 during endoscopy, and maximum desaturation from the baseline oxygen on air, were evaluated. There was no significant difference in the number of patients desaturating, minimum SpO2, or in the maximum desaturation from the baseline between the groups receiving intranasal or intrapharyngeal oxygen supplementation. In lower-risk patients receiving no supplementary oxygen (n = 27), ten patients (37%) desaturated, compared with one of 52 patients (2%) receiving supplementary oxygen (p < 0.001). There was also a significant difference between these groups in the minimum SpO2 (91% vs 97%, p < 0.001) and the maximum desaturation from the baseline (-5.2% vs +0.7%, p < 0.001) during endoscopy. We conclude that the intranasal and intrapharyngeal methods of oxygen supplementation are of similar efficacy, and that supplementary oxygen significantly decreases the incidence of critical arterial oxygen desaturation that occurs even in healthy patients undergoing upper gastrointestinal endoscopy.