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.

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.

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.

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.

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.

Automated responsiveness test and bispectral index monitoring during propofol and propofol/N2O sedation.

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

Alfentanil infusion as a component of intravenous anaesthesia for coronary artery bypass surgery with "fast-track" recovery.

Alfentanil and propofol total intravenous anaesthesia was assessed in 25 patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass (CPB). A manually controlled alfentanil infusion, calculated from estimated lean body mass and published pharmacokinetic data, was effective in achieving target plasma concentrations, while the "Diprifusor" system was used to vary propofol target concentrations according to changes in haemodynamics and anaesthetic requirement. The effects of CPB on alfentanil plasma concentrations were offset by changes in protein binding and free-fraction of the drug. With the use of only two target plasma concentrations for alfentanil (changed after CPB), a pre-determined infusion profile ensured effective plasma concentrations during surgery and concentrations unlikely to inhibit extubation within six hours of sternal closure.

N-acetylcysteine infusion alters blood redox status but not time to fatigue during intense exercise in humans.

Infusion of the antioxidant N-acetylcysteine (NAC) reduces fatigability in electrically evoked human muscle contraction, but due to reported adverse reactions, no studies have investigated NAC infusion effects during voluntary exercise in humans. We investigated whether a modified NAC-infusion protocol (125 mg. kg(-1). h(-1) for 15 min, then 25 mg. kg(-1). h(-1)) altered blood redox status and enhanced performance during intense, intermittent exercise. Eight untrained men participated in a counterbalanced, double-blind, crossover study in which they received NAC or saline (control) before and during cycling exercise, which comprised three 45-s bouts and a fourth bout that continued to fatigue, at 130% peak oxygen consumption. Arterialized venous blood was analyzed for glutathione status, hematology, and plasma electrolytes. NAC infusion induced no severe adverse reactions. Exercise decreased the reduced glutathione (P < 0.005) and increased oxidized glutathione concentrations (P < 0.005); NAC attenuated both effects (P < 0.05). NAC increased the rise in plasma K(+) concentration-to-work ratio (P < 0.05), indicating impaired K(+) regulation, although time to fatigue was unchanged (NAC 102 +/- 45 s; saline 107 +/- 53 s). Thus NAC infusion altered blood redox status during intense, intermittent exercise but did not attenuate fatigue.

Remifentanil concentration during target-controlled infusion of propofol.

After institutional approval and with written informed consent, eight surgical patients were infused intravenously with remifentanil at 250 ngkg lean body mass (LBM)(-1) x min(-1) for 30 min. Cardiovascular and respiratory parameters were recorded and arterial blood samples were taken at regular intervals. In each patient, the same protocol was repeated 40 min later during propofol infused to a target concentration of 3.0 microg x ml(-1). Blood concentrations of remifentanil and propofol were assayed using capillary gas chromatography and high performance liquid chromatography techniques respectively. The number of subjects enrolled was determined by testing the successive areas under the remifentanil time-concentration curve (AUC) for significant difference or non-difference using sequential analysis. The median measured propofol concentration was 3.5 (range: 2.6-4.5) microg x ml(-1) which did not change significantly during the second remifentanil infusion. The median AUC during propofol infusion was greater than control in all subjects, although there was considerable variation of 94.4 (64.3-129.6) versus 64.6 (34.8-126.9) ng x ml(-1) x min; P=0.008, n=8. After 30 min, there was no significant difference in remifentanil concentration during propofol infusion when compared with remifentanil alone of 4.6 (3.2-5.7) versus 3.8 (1.6-4.9) ng x ml(-1); P=0.73, n=8. Co-administration of propofol and remifentanil may result in greater remifentanil concentrations than when remifentanil is infused alone.

Determination of remifentanil in human blood by capillary gas chromatography with nitrogen-selective detection.

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%.

Buspirone and meperidine synergistically reduce the shivering threshold.

UNLABELLED: Mild hypothermia (i.e., 34 degrees C) may prove therapeutic for patients with stroke, but it usually provokes shivering. We tested the hypothesis that the combination of buspirone (a serotonin 1A partial agonist) and meperidine synergistically reduces the shivering threshold (triggering tympanic membrane temperature) to at least 34 degrees C while producing little sedation or respiratory depression. Eight volunteers each participated on four randomly-assigned days: 1) large-dose oral buspirone (60 mg); 2) large-dose IV meperidine (target plasma concentration of 0.8 microg/mL); 3) the combination of buspirone (30 mg) and meperidine (0.4 microg/mL); and 4) a control day without drugs. Core hypothermia was induced by infusion of lactated Ringer's solution at 4 degrees C. The control shivering threshold was 35.7 degrees C +/- 0.2 degrees C. The threshold was 35.0 degrees C +/- 0.8 degrees C during large-dose buspirone and 33.4 degrees C +/- 0.3 degrees C during large-dose meperidine. The threshold during the combination of the two drugs was 33.4 degrees C +/- 0.7 degrees C. There was minimal sedation on the buspirone and combination days and mild sedation on the large-dose meperidine day. End-tidal PCO2 increased approximately 10 mm Hg with meperidine alone. Buspirone alone slightly reduced the shivering threshold. The combination of small-dose buspirone and small-dose meperidine acted synergistically to reduce the shivering threshold while causing little sedation or respiratory toxicity. IMPLICATIONS: Mild hypothermia may be an effective treatment for acute stroke, but it usually triggers shivering, which could be harmful. Our results indicate that the combination of small-dose buspirone and small-dose meperidine acts synergistically to reduce the shivering threshold while causing little sedation or respiratory toxicity. This combination may facilitate the induction of therapeutic hypothermia in stroke victims.