Accuracy of dispersing tramadol capsules for oral administration in young children.

Tramadol is used in children aged <12 years for analgesia, particularly for those at risk of obstructive sleep apnoea undergoing adenotonsillectomy. The Australian Therapeutic Goods Administration have strongly recommended that oral tramadol drops (100 mg/ml) not be used in children <12 years because of the risk of inadvertent overdose. The total mass of drug in a 10 ml bottle is 1000 mg. The only alternative preparation available is a 50 mg capsule that requires dispersion of a capsule's contents should smaller doses be required. The accuracy of this preparation has not been assessed. Twenty surgical ward nurses were asked to prepare a 15 mg dose of tramadol from a 50 mg capsule. The dose was within ±5% of 15 mg in 13 cases (65%) and within ±10% in 19 cases (95%) (range 13.9-17.1 mg). Despite the dose variability of this method of preparing tramadol, we consider it sufficiently accurate for clinical use. We also consider it safe, as even at the highest dose prepared, the variability would be unlikely to contribute to clinically significant side-effects or toxicity. Moreover, the maximal dose that could be administered is limited to the size of the capsule (50 mg).

Sequencing of genes involved in the movement of calcium across human skeletal muscle sarcoplasmic reticulum: continuing the search for genes associated with malignant hyperthermia.

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.

Analysis of the entire ryanodine receptor type 1 and alpha 1 subunit of the dihydropyridine receptor (CACNA1S) coding regions for variants associated with malignant hyperthermia in Australian families.

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.

Glutamate quantification in patients with supratentorial gliomas using chemical shift imaging.

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 < 0.0001, respectively). There was a modest, but statistically significant, correlation between the ex vivo measured Glu and in vivo spectroscopic Glu concentration (r² = 0.22, p = 0.04) and ratios of Glu to Cr (r² = 0.30, p = 0.002). Quantitative measurement of Glu content is feasible in patients with supratentorial gliomas using CSI. The in vitro and in vivo results suggest that this has the potential to be a reliable quantitative imaging assay for brain tumor patients. This may have wide clinical research applications in a number of neurological disorders where Glu excitotoxicity and metabolic dysfunction are known to play a role in pathogenesis, including tumor associated epilepsy, epilepsy, stroke and neurotrauma.

Plasma ropivacaine concentrations during bilateral transversus abdominis plane infusions.

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.

Symptomatic local anaesthetic toxicity and plasma ropivacaine concentrations after transversus abdominis plane block for Caesarean section.

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.

Cardiac output and propofol concentrations in prone surgical patients.

The aim of this study was to compare cardiac output and plasma propofol concentrations in the supine and prone positions in healthy adult patients presenting for lumbar spine surgery. Patients received propofol and remifentanil via effect-site steered target-controlled infusions. Cardiac output and plasma propofol concentration were compared during 20 minutes in the supine position and 20 minutes after positioning on a Wilson frame. Cardiac output did not change significantly over 20 minutes in either position (P = 0.37) and was similar at 20 minutes in the supine (6.1 [1.6] l/minute) and prone positions (6.1 [1.9] l/minute) (P = 0.87). Propofol concentrations were similar in the supine and prone positions at 20 minutes (2.55 [0.89] and 2.53 [0.90] microg/ml; P = 0.93). We conclude that prone positioning on the Wilson frame does not affect cardiac output or plasma propofol concentration.

Plasma ropivacaine concentrations after ultrasound-guided transversus abdominis plane block.

BACKGROUND: The transversus abdominis plane block is a novel technique involving injection of local anaesthetic between the internal oblique and the transversus abdominis muscles of the abdominal wall. It is possible that injection of a large dose of local anaesthetic into a relatively vascular plane may result in toxic concentrations. One previously published study examined plasma lidocaine concentrations after transversus abdominus plane block and showed potentially toxic plasma concentrations. Although ropivacaine is most commonly used for this technique, plasma concentrations of ropivacaine after this block have not been reported previously. METHODS: Adult female patients undergoing elective open gynaecological surgery received bilateral ultrasound-guided transverse abdominal plane blocks before surgical incision (3 mg kg(-1) of ropivacaine diluted to 40 ml). Venous blood was collected each 15 min for the first hour, each 30 min for the second hour, and then at 3, 4, 12, and 24 h post-block. RESULTS: Twenty-eight patients were recruited. The mean (sd) peak total ropivacaine concentration occurred 30 min post-injection and was 2.54 (sd 0.75) µg ml(-1). The highest measured concentration was 4.00 µg ml(-1), also 30 min post-injection. Mean total concentrations remained above 2.20 µg ml(-1) for up to 90 min post-injection. The mean unbound peak venous concentration was 0.14 (0.05) µg ml(-1), and the peak was 0.25 µg ml(-1). CONCLUSIONS: Transversus abdominus plane block using 3 mg kg(-1) of ropivacaine produces venous plasma concentrations that are potentially neurotoxic, although broadly consistent with plasma levels found after injection at other comparable sites.

A comparison of parametric and non-parametric approaches to target-controlled infusion of propofol.

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 x min(-1) x kg(LBM)(-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 V = 0.102 (0.0155) l/kg(LBM), V2 = 0.257 (0.079) l/kg(LBM), 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 x min(-1) x kg(LBM)(-1). The only significant covariate was LBM. Within infusion data improved prediction when compared with data derived in previous studies from random observations.

Cardiovascular testing in Fabry disease: exercise capacity reduction, chronotropic incompetence and improved anaerobic threshold after enzyme replacement.

AIM: The aim of this study was to document exercise capacity and serial electrocardiogram and echocardiograph findings in a cohort of Australian patients with Fabry disease, in relation to their history of enzyme replacement therapy (ERT). BACKGROUND: Fabry disease has multifactorial effects on the cardiovascular system. Most previous studies have focused on electrocardiographic and echocardiographic parameters. Exercise capacity can be used as an integrated measure of cardiovascular function and allows the effects of treatment to be monitored. METHODS: A total of 38 patients (30 men and 8 women) with Fabry disease were monitored by 12-lead electrocardiograms every 6-12 months, and by annual standardized-protocol echocardiograms. Bicycle stress tests with VO(2) max measurement and once-only 6 minutes' walk tests were also carried out in subsets of patients whose general health status allowed testing. RESULTS: Seventy per cent of patients met electrocardiogram criteria for left ventricular hypertrophy. Left ventricular hypertrophy on echocardiograph was present in 64% of patients (80% of men). Exercise capacity was reduced in patients with Fabry disease compared with that predicted from normative population data. Mild improvement in anaerobic threshold was seen in the first year of ERT (14.1 +/- 3.0 to 15.8 +/- 3.0, P = 0.02), but no consistent further increase was seen beyond the first year. Most patients had resting bradycardia, with impaired ability to increase heart rate during exercise. Serial testing on ERT showed an improvement in anaerobic threshold but no significant change in VO(2) max. CONCLUSIONS: Male patients with Fabry disease were unable to attain predicted maximal heart rate on exercise or to achieve normal exercise levels. ERT was associated with a small improvement in anaerobic threshold over the first year.

Identification of genetic mutations in Australian malignant hyperthermia families using sequencing of RYR1 hotspots.

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 'hot-spots' 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.

Autonomic effects of epidural and intravenous fentanyl.

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.

Pharmacokinetics of levobupivacaine after caudal epidural administration in infants less than 3 months of age.

BACKGROUND: There are few data describing levobupivacaine pharmacokinetics in infants (<3 months) after caudal administration. 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%) microg ml(-1) for total levobupivacaine and 0.09 (CV 37%) microg 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.

Pethidine and skin warming to prevent shivering during endovascular cooling.

We tested the efficacy of pethidine and cutaneous warming to prevent shivering during percutaneous cooling in unanaesthetized patients. Ten patients scheduled for cranial neurosurgery received pethidine infusion and skin warming. The Setpoint internal heat-exchanging catheter was inserted and cooling to 33.5 degrees C was started. Clonidine and chlorpromazine were given as "rescue medication" to treat shivering. General anaesthesia was planned to be induced after cooling was complete. Rewarming was initiated at dural closure. Three patients successfully completed the protocol, cooling to 33.8 degrees C at a median rate of 3.6 (range: 3.4-3.8) degrees C/h. Two patients cooled to 33.8 degrees C but required treatment for shivering (cooling rate: 2.9 [2.8-3.1] degrees C/h). Four patients failed to cool adequately because of refractory shivering (cooling rate: 20 [1.5-2.9] degrees C/h). One patient did not shiver and yet failed to cool adequately (cooling rate: 0.76 degrees C/h). Rewarming was at a rate of 26 (1.2-4.3) degrees C/h. There were no significant complications arising from catheter placement. The combination of skin warming and pethidine was not reliable enough to be recommended for use during endovascular cooling in unanaesthetized patients.

N-acetylcysteine enhances muscle cysteine and glutathione availability and attenuates fatigue during prolonged exercise in endurance-trained individuals.

The production of reactive oxygen species in skeletal muscle is linked with muscle fatigue. This study investigated the effects of the antioxidant compound N-acetylcysteine (NAC) on muscle cysteine, cystine, and glutathione and on time to fatigue during prolonged, submaximal exercise in endurance athletes. Eight men completed a double-blind, crossover study, receiving NAC or placebo before and during cycling for 45 min at 71% peak oxygen consumption (VO2 peak) and then to fatigue at 92% VO2 peak. NAC was intravenously infused at 125 mg.kg(-1).h(-1) for 15 min and then at 25 mg.kg(-1).h(-1) for 20 min before and throughout exercise. Arterialized venous blood was analyzed for NAC, glutathione status, and cysteine concentration. A vastus lateralis biopsy was taken preinfusion, at 45 min of exercise, and at fatigue and was analyzed for NAC, total glutathione (TGSH), reduced glutathione (GSH), cysteine, and cystine. Time to fatigue at 92% VO2 peak was reproducible in preliminary trials (coefficient of variation 5.6 +/- 0.6%) and with NAC was enhanced by 26.3 +/- 9.1% (NAC 6.4 +/- 0.6 min vs. Con 5.3 +/- 0.7 min; P <0.05). NAC increased muscle total and reduced NAC at both 45 min and fatigue (P <0.005). Muscle cysteine and cystine were unchanged during Con, but were elevated above preinfusion levels with NAC (P <0.001). Muscle TGSH (P <0.05) declined and muscle GSH tended to decline (P=0.06) during exercise. Both were greater with NAC (P <0.05). Neither exercise nor NAC affected whole blood TGSH. Whereas blood GSH was decreased and calculated oxidized glutathione increased with exercise (P <0.05), both were unaffected by NAC. In conclusion, NAC improved performance in well-trained individuals, with enhanced muscle cysteine and GSH availability a likely mechanism.

Comparison of disposable and reusable laryngeal mask airways in spontaneously ventilating adult patients.

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.

A new system to target the effect-site during propofol sedation.

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.